Adenoviridae

Adenoviruses

Transmission electron micrograph of two adenovirus particles

Virus classification Virus group: Group I (dsDNA) Family: Adenoviridae Genera Atadenovirus Aviadenovirus Ichtadenovirus Mastadenovirus Siadenovirus Adenoviruses are medium-sized (90100 nm), nonenveloped (without an outer lipid bilayer) icosahedralviruses composed of a nucleocapsid and a double-stranded linear DNA genome. There are 55 described serotypes in humans, which are responsible for 510% of upper respiratory infections in children, and many infections in adults as well. Viruses of the familyAdenoviridae infect various species of vertebrates, including humans. Adenoviruses were first isolated in 1953 from human adenoids. They are classified as group I under the Baltimore classification scheme, meaning their genomes consist of double stranded DNA.

Virology
Classification
This family contains the following genera:
y y y y y

Genus Atadenovirus; type species: Ovine adenovirus D Genus Aviadenovirus; type species: Fowl adenovirus A Genus Ichtadenovirus; type species: Sturgeon adenovirus A Genus Mastadenovirus; type species: Human adenovirus C; others include AD-36 Genus Siadenovirus; type species: Frog adenovirus

Diversity
Classification of Adenoviridae can be complex. In humans, there are 56 accepted human adenovirus types (HAdV-1 to 56) in seven species (Human adenovirus A to G):[1]
y y y y y y y

A: 12, 18, 31 B: 3, 7, 11, 14, 16, 21, 34, 35, 50, 55 C: 1, 2, 5, 6 D: 8, 9, 10, 13, 15, 17, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 33, 36, 37, 38, 39, 42, 43, 44, 45, 46, 47, 48, 49, 51, 53, 54, 56[2] E: 4 F: 40, 41 G: 52[3]

Different types/serotypes are associated with different conditions:

y y y

respiratory disease (mainly species HAdV-B and C) conjunctivitis (HAdV-B and D) gastroenteritis (HAdV-F types 40, 41, HAdV-G type 52)

When not restricting the subject to human viruses, Adenoviridae can be divided into five genera: Mastadenovirus, Aviadenovirus, Atadenovirus, Siadenovirus, and Ichtadenovirus.[1]

Structure
Adenoviruses represent the largest nonenveloped viruses. Because of their large size, they are able to be transported through the endosome (i.e., envelope fusion is not necessary). The virion also has a unique "spike" or fiber associated with each penton base of the capsid (see picture below) that aids in attachment to the host cell via the coxsackie-adenovirus receptor on the surface of the hostcell.

In 2010, scientists announced that they had solved the structure of the human adenovirus at the atomic level, making the largest high-resolution model ever. The virus is composed of around 1 million amino acid residues and weighs around 150 MDa.[4][5]

Genome

Schematic diagram of the linear adenovirus genome, showing Early genes (E) and Late genes (L). The adenovirus genome is linear, non-segmented double-stranded (ds) DNA that is between 26 and 45 Kbp. This allows the virus to theoretically carry 22 to 40 genes. Although this is significantly larger than other viruses in its Baltimore group, it is still a very simple virus and is heavily reliant on the host cell for survival and replication. An interesting feature of this viral genome is that it has a terminal 55 kDa protein associated with each of the 5' ends of the linear dsDNA. These are used as primers in viral replication and ensure that the ends of the virus' linear genome are adequately replicated.

Replication

Adenoviruses possess a linear dsDNAgenome and are able to replicate in the nucleus of mammalian cells using the hosts replication machinery.

The structure of adenovirus. 1 = penton capsomeres 2 = hexoncapsomeres, and 3= viral genome (linear dsDNA) Entry of adenoviruses into the host cell involves two sets of interactions between the virus and the host cell. Most of the action occurs at the vertices. Entry into the host cell is initiated by the knob domain of the fiber protein binding to the cell receptor. The two currently established receptors are: CD46 for the group B human adenovirus serotypes and the coxsackievirus adenovirus receptor (CAR) for all other serotypes. There are some reports suggesting MHC molecules and sialic acid residues functioning in this capacity as well. This is followed by a secondary interaction, where a specialized motif in the penton base protein interacts with an integrin molecule. It is the co-receptor interaction that stimulates internalization of the adenovirus. This co-receptor molecule is v integrin. Binding to v integrin results in endocytosis of the virus particle via clathrin-coated pits. Attachment to v integrin stimulates cell signaling and thus induces actin polymerization resulting in entry of the virion into the host cell within an endosome.[6] Once the virus has successfully gained entry into the host cell, the endosome acidifies, which alters virus topology by causing capsid components to disassociate. These changes as well as the toxic nature of the pentons result in the release of the virion into the cytoplasm. With the help of cellular microtubules, the virus is transported to the nuclear pore complex, whereby the adenovirus particle disassembles. Viral DNA is subsequently released, which can enter the nucleus via the nuclear pore.[7] After this the DNA associates with histone molecules. Thus, viral gene expression can occur and new virus particles can be generated.

The adenovirus life cycle is separated, by the DNA replication process, into two phases: an early and a late phase. In both phases, a primary transcript that is alternatively spliced to generate monocistronic mRNAs compatible with the hosts ribosome is generated, allowing for the products to be translated. The early genes are responsible for expressing mainly non-structural, regulatory proteins. The goal of these proteins is threefold: to alter the expression of host proteins that are necessary for DNA synthesis; to activate other virus genes (such as the virus-encoded DNA polymerase); and to avoid premature death of the infected cell by the host-immune defenses (blockage of apoptosis, blockage of interferon activity, and blockage of MHC class I translocation and expression). Some adenoviruses under specialized conditions can transform cells using their early gene products. E1a (binds Retinoblastoma tumor suppressor protein) has been found to immortalize primary cells in vitro allowing E1b (binds p53 tumor suppressor) to assist and stably transform the cells. Nevertheless, they are reliant upon each other to successfully transform the host cell and form tumors. DNA replication separates the early and late phases. Once the early genes have liberated adequate virus proteins, replication machinery, and replication substrates, replication of the adenovirus genome can occur. A terminal protein that is covalently bound to the 5 end of the adenovirus genome acts as a primer for replication. The viral DNA polymerase then uses a strand displacement mechanism, as opposed to the conventional Okazaki fragments used in mammalian DNA replication, to replicate the genome. The late phase of the adenovirus lifecycle is focused on producing sufficient quantities of structural protein to pack all the genetic material produced by DNA replication. Once the viral components have successfully been replicated, the virus is assembled into its protein shells and released from the cell as a result of virally induced cell lysis.

Epidemiology
Transmission
Adenoviruses are unusually stable to chemical or physical agents and adverse pH conditions, allowing for prolonged survival outside of the body and water. Adenoviruses are spread primarily via respiratory droplets, however they can also be spread by fecal routes as well.

Humans
Humans infected with adenoviruses display a wide range of responses, from no symptoms at all to the severe infections typical of Adenovirus serotype 14.

Animals

Two types of canine adenoviruses are well known, type 1 and 2. Type 1 causes infectious canine hepatitis, a potentially fatal disease involving vasculitis and hepatitis. Type 1 infection can also cause respiratory and eye infections. Canine adenovirus 2 (CAdV-2) is one of the potential causes of kennel cough. Core vaccines for dogs include attenuated live CAdV-2, which produces immunity to CAdV-1 and CAdV-2. CAdV-1 was initially used in a vaccine for dogs, but cornealedema was a common complication.[8] Adenovirus in Reptiles has little known about it, but research is currently in progress. Adenoviruses are also known to cause respiratory infections in horses, cattle, pigs, sheep, and goats. Equine adenovirus 1 can also cause fatal disease in immunocompromisedArabian foals, involving pneumonia and destruction of pancreatic and salivary gland tissue.[8]

Prevention
In the past, US military recruits were vaccinated against two serotypes of adenotypes, with a corresponding decrease in illnesses caused by those serotypes. The vaccine is no longer manufactured, and there are currently no vaccines available to protect against the adenovirus. Good hygiene, including handwashing, is still the best way to avoid picking up the adenovirus from an infected person.

Infections
Most infections with adenovirus result in infections of the upper respiratory tract. Adenovirus infections often show up as conjunctivitis, tonsilitis (which may look exactly like strep throat and cannot be distinguished from strep except by throat culture), an ear infection, or croup. Adenoviruses can also cause gastroenteritis (stomach flu). A combination of conjunctivitis and tonsilitis is particularly common with adenovirus infections. Some children (especially small ones) can develop adenovirus bronchiolitis or pneumonia, both of which can be severe. In babies, adenoviruses can also cause coughing fits that look almost exactly like whooping cough. Adenoviruses can also cause viral meningitis or encephalitis. Rarely, adenovirus can cause hemorrhagic cystitis (inflammation of the urinary bladdera form of urinary tract infection with blood in the urine). Most people recover from adenovirus infections by themselves, but people with immunodeficiency sometimes die of adenovirus infections, and rarely even previously healthy people can die of these infections.[9] Adenoviruses are often transmitted by coughed-out droplets, but can also be transmitted by contact with an infected person, or by virus particles left on objects such as towels and faucet handles. Some people with adenovirus gastroenteritis may shed the virus in their stools for months after getting over the symptoms. The virus can be passed from one person to another through some sexual practices, and through water in swimming pools that do not have enough chlorine in them. As with many other illnesses, good handwashing is one way to lessen the

spread of adenoviruses from one person to another. Heat and bleach will kill adenoviruses on objects.

Treatment
There are no antiviral drugs to treat adenoviral infections, so treatment is largely directed at the symptoms (such as acetaminophen for fever). A doctor may give antibiotic eyedrops for conjunctivitis, since it takes a while to test to see if the eye infection is bacterial or viral and to help prevent secondary bacterial infections.

Utilization in treatment of unrelated diseases

Adenovirus is used as a vehicle to administer targeted therapy,[10] in the form of recombinant DNA or protein. Specific modifications on fibre proteins are used to target Adenovirus to certain cell types;[11] a major effort is made to limit hepatotoxicity and prevent multiple organ failure. Adenovirus dodecahedron can qualify as a potent delivery platform for foreign antigens to human myeloid dendritic cells (MDC), and that it is efficiently presented by MDC to M1specific CD8+ T lymphocytes.

Retrovirus
Retroviruses Virus classification Group: Family: Group VI (ssRNA-RT) Retroviridae Genera Subfamily: Orthoretrovirinae Alpharetrovirus Betaretrovirus Gammaretrovirus Deltaretrovirus Epsilonretrovirus Lentivirus Subfamily: Spumaretrovirinae Spumavirus A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA. Retroviruses are enveloped viruses that belong to the viral family Retroviridae. A special variant of retroviruses are endogenous retroviruses which are integrated into the genome of the host and inherited across generations. The virus itself stores its nucleic acid in the form of a +mRNA (including the 5'cap and 3'PolyA inside the virion) genome and serves as a means of delivery of that genome into cells it targets as an obligate parasite, and constitutes the infection. Once in the host's cell, the RNA strands

undergo reverse transcription in the cytoplasm and are integrated into the host's genome, at which point the retroviral DNA is referred to as a provirus. It is difficult to detect the virus until it has infected the host. In most viruses, DNA is transcribed into RNA, and then RNA is translated into protein. However, retroviruses function differently - their RNA is reverse-transcribed into DNA, which is integrated into the host cell's genome (when it becomes a provirus), and then undergoes the usual transcription and translational processes to express the genes carried by the virus. Therefore, the order of steps from a retroviral gene to a retroviral protein is: RNA DNA RNA protein. This differs from the initial view of Francis Crick and James Watson. In their view, only a single-direction pathway was possible: DNA RNA protein.

Structure
Virions of retroviruses consist of enveloped particles about 100 nm in diameter. The virions also contain two identical single-stranded RNA molecules 7-10 kilobases (kb) in length. Although virions of different retroviruses do not have the same morphology or biology, all the virion components are very similar.[1] The main virion components are:
y

Envelope: composed of lipids obtained from the host plasma membrane during budding process as well as glycoproteins encoded by the env gene. RNA: consists of a dimer RNA. It has a cap at 5' end and polyadenyle at 3' end. The RNA genome also has terminal noncoding regions, which are important in replication, and internal regions that encode virion proteins for gene expression. The 5' end includes four regions, which are R, U5, PBS, and L. R region is a short repeated sequence at each end of the genome during the reverse transcription in order to ensure correct end-to-end transfer in growing chain. U5, on the other hand, is a short unique sequence between R and PBS. PBS (primer binding site) consists of 18 bases complementary to 3' end of tRNA primer. L region is an untranslated leader region that gives signal for packaging of genome RNA. The 3' end includes 3 regions, which are PPT (polypurine tract), U3, and R. PPT is primer for plusstrand DNA synthesis during reverse transcription. U3 is a sequence between PPT and R, which has signal that provirus can use in transcription. R is the terminal repeated sequence at 3' end. Proteins: consisted of gag proteins, protease (PR), pol proteins and env proteins. Gag proteins are major components of the viral capsid, which are about 2000-4000 copies per virion. Protease is expressed differently in different viruses. It functions in proteolytic cleavages during virion maturation to make mature gag and pol proteins. Pol proteins are responsible for synthesis of viral DNA and integration into host DNA after infection. Finally, env proteins play role in association and entry of virion into the host cell.[2]

Multiplication

When retroviruses have integrated their own genome into the germ line, their genome is passed on to a following generation. These endogenous retroviruses (ERVs), contrasted with exogenous ones, now make up 5-8% of the human genome.[3] Most insertions have no known function and are often referred to as "junk DNA". However, many endogenous retroviruses play important roles in host biology, such as control of gene transcription, cell fusion during placental development in the course of the germination of an embryo, and resistance to exogenous retroviral infection. Endogenous retroviruses have also received special attention in the research of immunology-related pathologies, such as autoimmune diseases like multiple sclerosis, although endogenous retroviruses have not yet been proven to play any causal role in this class of disease.[4] While transcription was classically thought to only occur from DNA to RNA, reverse transcriptase transcribes RNA into DNA. The term "retro" in retrovirus refers to this reversal (making DNA from RNA) of the central dogma of molecular biology. Reverse transcriptase activity outside of retroviruses has been found in almost all eukaryotes, enabling the generation and insertion of new copies of retrotransposons into the host genome. These inserts are transcribed by enzymes of the host into new RNA molecules that enter the cytosol. Next, some of these RNA molecules are translated into viral proteins. For example, the gag gene is translated into molecules of the capsid protein, the pol gene is transcribed into molecules of reverse transcriptase, and the env gene is translated into molecules of the envelope protein. It is important to note that a retrovirus must "bring" its own reverse transcriptase in its capsid, otherwise it is unable to utilize the enzymes of the infected cell to carry out the task, due to the unusual nature of producing DNA from RNA. Industrial drugs that are designed as protease and reverse transcriptase inhibitors can quickly be proved ineffective because the gene sequences that code for the protease and the reverse transcriptase can undergo many substitutions. These substitutions of nitrogenous bases, which make up the DNA strand, can make either the protease or the reverse transcriptase difficult to attack. The amino acid substitution enables the enzymes to evade the drug regimens because mutations in the gene sequences can cause physical or chemical change, which makes them harder to detect by the drug. When the drugs that are supposed to attack enzymes, such as protease, are designed, the manufacturers target specific sites on the enzyme. One way to attack these targets can be through hydrolysis of molecular bonds, which means that the drug will add molecules of H2O (water) to specific bonds. By adding molecules of water at a site on the virus, the drug breaks the previous bonds that were linked to each other. If several of these breaks occur, the result can lead to lysis, the death of the virus.[5] Because reverse transcription lacks the usual proofreading of DNA replication, a retrovirus mutates very often. This enables the virus to grow resistant to antiviral pharmaceuticals quickly, and impedes the development of effective vaccines and inhibitors for the retrovirus.[6] One drawback of retroviruses, such as the Moloney retrovirus, involves the requirement for cells to be actively dividing for transduction. As a result, cells such as neurons are very resistant to infection and transduction by retroviruses. There is concern that insertional mutagenesis due to integration into the host genome might lead to cancer or leukemia. This is unlike Lentiviridae, a

subclass of Retroviridae which are able to integrate their RNA into the genome of non-dividing host cells.

Genes
Retrovirus genomes commonly contain these three open reading frames that encode for proteins that can be found in the mature virus:
y y y

group-specific antigen (gag) codes for core and structural proteins of the virus; polymerase (pol) codes for reverse transcriptase, protease and integrase; and, envelope (env) codes for the retroviral coat proteins.

Provirus
This DNA can be incorporated into host genome as a provirus that can be passed on to progeny cells. The retrovirus DNA is inserted at random into the host genome. Because of this, it can be inserted into oncogenes. In this way some retroviruses can convert normal cells into cancer cells. Some provirus remains latent in the cell for a long period of time before it is activated by the change in cell environment.

Development
Studies of retroviruses led to the first demonstrated synthesis of DNA from RNA templates, a fundamental mode for transferring genetic material that occurs in both eukaryotes and prokaryotes. It has been speculated that the RNA to DNA transcription processes used by retroviruses may have first caused DNA to be used as genetic material. In this model, the RNA world hypothesis, cellular organisms adopted the more chemically stable DNA when retroviruses evolved to create DNA from the RNA templates. Retroviruses are proving to be valuable research tools in molecular biology and have been used successfully in gene delivery systems.[7]

Gene therapy
Gammaretroviral and lentiviral vectors for gene therapy have been developed that mediate stable genetic modification of treated cells by chromosomal integration of the transferred vector genomes. This technology is of use, not only for research purposes, but also for clinical gene therapy aiming at the long-term correction of genetic defects, e.g., in stem and progenitor cells. Retroviral vector particles with tropism for various target cells have been designed. Gammaretroviral and lentiviral vectors have so far been used in more than 300 clinical trials, addressing treatment options for various diseases.[7][8]

Cancer
Retroviruses that cause tumor growth include Rous sarcoma virus and mouse mammary tumor virus. Cancer can be triggered by proto-oncogenes that were mistakenly incorporated into

proviral DNA or by the disruption of cellular proto-oncogenes. Rous sarcoma virus contains the src gene that triggers tumor formation. Later it was found that a similar gene in cells is involved in cell signaling, which was most likely excised with the proviral DNA. Nontransforming viruses can randomly insert their DNA into proto-oncogenes, disrupting the expression of proteins that regulate the cell cycle. The promoter of the provirus DNA can also cause over expression of regulatory genes.

Classification

Phylogeny of Retroviruses

Exogenous
The following genera are included here:
y y y y

Genus Alpharetrovirus; type species: Avian leukosis virus; others include Rous sarcoma virus Genus Betaretrovirus; type species: Mouse mammary tumour virus Genus Gammaretrovirus; type species: Murine leukemia virus; others include Feline leukemia virus Genus Deltaretrovirus; type species: Bovine leukemia virus; others include the cancercausing Human T-lymphotropic virus

y y y

Genus Epsilonretrovirus; type species: Walleye dermal sarcoma virus Genus Lentivirus; type species: Human immunodeficiency virus 1; others include Simian, Feline immunodeficiency viruses Genus Spumavirus; type species: Simian foamy virus

These were previously divided into three subfamilies (Oncovirinae, Lentivirinae, and Spumavirinae), but with current knowledge of retroviruses, this is no longer appropriate. (The term oncovirus is still commonly used, though.)

Endogenous
Main article: endogenous retrovirus Endogenous retroviruses are not formally included in this classification system, and are broadly classified into three classes, on the basis of relatedness to exogenous genera:
y y y

Class I are most similar to the gammaretroviruses Class II are most similar to the betaretroviruses and alpharetroviruses Class III are most similar to the spumaviruses

Group VI
All members of Group VI use virally encoded reverse transcriptase, an RNA-dependent DNA polymerase, to produce DNA from the initial virion RNA genome. This DNA is often integrated into the host genome, as in the case of retroviruses and pseudoviruses, where it is replicated and transcribed by the host. Group VI includes:
y y y

Family Metaviridae Family Pseudoviridae Family Retroviridae - Retroviruses, e.g. HIV

Group VII
Both families in Group VII have DNA genomes contained within the invading virus particles. The DNA genome is transcribed into both mRNA, for use as a transcript in protein synthesis, and pre-genomic RNA, for use as the template during genome replication. Virally encoded reverse transcriptase uses the pre-genomic RNA as a template for the creation of genomic DNA. Group VII includes:
y y

Family Hepadnaviridae - e.g. Hepatitis B virus Family Caulimoviridae - e.g. Cauliflower mosaic virus

Treatment
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. Different classes of antiretroviral drugs act on different stages of the HIVlife cycle. Combination of several (typically three or four) antiretroviral drugs is known as highly active anti-retroviral therapy (HAART).

Treatment of veterinary retroviruses

Feline Leukemia Virus and Feline immunodeficiency virus infections are treated with biologics, including Lymphocyte T-Cell Immune Modulator (LTCI)[9] marketed by IMULAN BioTherapeutics, LLC.

HIV
HIV
Classification and external resources

Diagram of HIV

ICD-10

B20-B24

ICD-9

042-044

OMIM

609423

MedlinePlus

000602

eMedicine

article/783434

MeSH

D006678

Human immunodeficiency virus (HIV) is a lentivirus (a member of the retrovirus family) that causes acquired immunodeficiency syndrome (AIDS),[1][2] a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, preejaculate, or breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells. The four major routes of transmission are unsafe sex, contaminated needles, breast milk, and transmission from an infected mother to her baby at birth (perinatal transmission). Screening of blood products for HIV has largely eliminated transmission through blood transfusions or infected blood products in the developed world. HIV infection in humans is considered pandemic by the World Health Organization (WHO). Nevertheless, complacency about HIV may play a key role in HIV risk.[3][4] From its discovery in 1981 to 2006, AIDS killed more than 25 million people.[5] HIV infects about 0.6% of the world's population.[5] In 2009, AIDS claimed an estimated 1.8 million lives, down from a global peak of 2.1 million in 2004.[6] Approximately 260,000 children died of AIDS in 2009.[6] A disproportionate number of AIDS deaths occur in Sub-Saharan Africa, retarding economic growth and exacerbating the burden of poverty.[7] In 2005, it was estimated that HIV would infect 90 million people in Africa, resulting in a minimum estimate of 18 million orphans.[8] Treatment with antiretroviral drugs reduces both the mortality and the morbidity of HIV infection.[9] Although antiretroviral medication is still not universally available, expansion of antiretroviral therapy programmes since 2004 has helped to turn the tide of AIDS deaths and new infections in many parts of the world.[6] Intensified awareness and preventive measures, as well as the natural course of the epidemic, have also played a role. Nevertheless, an estimated 2.6 million people were newly infected in 2009.[6] HIV infects vital cells in the human immune system such as helper T cells (specifically CD4+ T cells), macrophages, and dendritic cells.[10] HIV infection leads to low levels of CD4+T cells through three main mechanisms: First, direct viral killing of infected cells; second, increased rates of apoptosis in infected cells; and third, killing of infected CD4+ T cells by CD8 cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections. Most untreated people infected with HIV-1 eventually develop AIDS.[11] These individuals mostly die from opportunistic infections or malignancies associated with the progressive failure

of the immune system.[12] HIV progresses to AIDS at a variable rate affected by viral, host, and environmental factors; most will progress to AIDS within 10 years of HIV infection: some will have progressed much sooner, and some will take much longer.[13][14] Treatment with antiretrovirals increases the life expectancy of people infected with HIV. Even after HIV has progressed to diagnosable AIDS, the average survival time with antiretroviral therapy was estimated to be more than 5 years as of 2005.[15] Without antiretroviral therapy, someone who has AIDS typically dies within a year.[16]
y

Classification
Comparison of HIV species Species Virulence Infectivity Prevalence HIV-1 High HIV-2 Lower High Low Global Inferred origin Common Chimpanzee

West Africa Sooty Mangabey

HIV is a member of the genusLentivirus,[17] part of the family of Retroviridae.[18]Lentiviruses have many morphologies and biological properties in common. Many species are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long incubation period.[19]Lentiviruses are transmitted as single-stranded, positive-sense, enveloped RNA viruses. Upon entry into the target cell, the viral RNAgenome is converted (reverse transcribed) into double-stranded DNA by a virally encoded reverse transcriptase that is transported along with the viral genome in the virus particle. The resulting viral DNA is then imported into the cell nucleus and integrated into the cellular DNA by a virally encoded integrase and host co-factors.[20] Once integrated, the virus may become latent, allowing the virus and its host cell to avoid detection by the immune system. Alternatively, the virus may be transcribed, producing new RNA genomes and viral proteins that are packaged and released from the cell as new virus particles that begin the replication cycle anew. Two types of HIV have been characterized: HIV-1 and HIV-2. HIV-1 is the virus that was initially discovered and termed both LAV and HTLV-III. It is more virulent, more infective,[21] and is the cause of the majority of HIV infections globally. The lower infectivity of HIV-2 compared to HIV-1 implies that fewer of those exposed to HIV-2 will be infected per exposure. Because of its relatively poor capacity for transmission, HIV-2 is largely confined to West Africa.[22]

Signs and symptoms

A generalized graph of the relationship between HIV copies (viral load) and CD4 counts over the average course of untreated HIV infection; any particular individual's disease course may vary considerably. CD4+ T cell count (cells per L) HIV RNA copies per mL of plasma Infection with HIV-1 is associated with a progressive decrease of the CD4+ T cell count and an increase in viral load, the level of HIV in the blood. The stage of infection can be determined by measuring the patient's CD4+ T cell count and viral load. The stages of HIV infection are acute infection (also known as primary infection), latency and AIDS. Acute infection lasts for several weeks and may include symptoms such as fever, lymphadenopathy (swollen lymph nodes), pharyngitis (sore throat), rash, myalgia (muscle pain), malaise, and mouth and esophageal sores. The latency stage involves few or no symptoms and can last anywhere from two weeks to twenty years or more, depending on the individual. AIDS, the final stage of HIV infection, is defined by low CD4+ T cell counts (fewer than 200 per microliter), various opportunistic infections, cancers and other conditions. A small percentage of HIV-1 infected individuals retain high levels of CD4+ T-cells without antiretroviral therapy. However, most have detectable viral load and will eventually progress to AIDS without treatment, albeit more slowly than others. These individuals are classified as HIV controllers or long-term nonprogressors (LTNP). People who maintain CD4+ T cell counts and also have low or clinically undetectable viral load without anti-retroviral treatment are known as elite controllers or elite suppressors (ES).[23][24]

Acute infection

Main symptoms of acute HIV infection. Infection with HIV generally occurs by introduction of bodily fluids from an infected person into the body of an uninfected person. A period of rapid viral replication ensues, leading to an abundance of virus in the peripheral blood. During primary infection, the level of HIV may reach several million virus particles per milliliter of blood.[25] This response is accompanied by a marked drop in the numbers of circulating CD4+ T cells. This acute viremia is associated in virtually all patients with the activation of CD8+ T cells, which kill HIV-infected cells, and subsequently with antibody production, or seroconversion. The CD8+ T cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4+ T cell counts rebound. A good CD8+ T cell response has been linked to slower disease progression and a better prognosis, though it does not eliminate the virus.[26] During this period (usually 24 weeks post-exposure) most individuals (80 to 90%) develop an influenza or mononucleosis-like illness called acute HIV infection, the most common symptoms of which may include fever, lymphadenopathy, pharyngitis, rash, myalgia, malaise, mouth and esophageal sores, and may also include, but less commonly, headache, nausea and vomiting,

enlarged liver/spleen, weight loss, thrush, and neurological symptoms. Infected individuals may experience all, some, or none of these symptoms. The duration of symptoms varies, averaging 28 days and usually lasting at least a week.[27] Because of the nonspecific nature of these symptoms, they are often not recognized as signs of HIV infection. Even if patients go to their doctors or a hospital, they will often be misdiagnosed as having one of the more common infectious diseases with the same symptoms. As a consequence, these primary symptoms are not used to diagnose HIV infection, as they do not develop in all cases and because many are caused by other more common diseases. However, recognizing the syndrome can be important because the patient is much more infectious during this period.[28]

Chronic infection
A strong immune defense reduces the number of viral particles in the blood stream, marking the start of secondary or chronic HIV infection. The secondary stage of HIV infection can vary between two weeks and 20 years. During this phase of infection, HIV is active within lymph nodes, which typically become persistently swollen, in response to large amounts of virus that become trapped in the follicular dendritic cells (FDC) network.[29] The surrounding tissues that are rich in CD4+ T cells may also become infected, and viral particles accumulate both in infected cells and as free virus. Individuals who are in this phase are still infectious. During this time, CD4+ CD45RO+ T cells carry most of the proviral load.[30] During this stage of infection early initiation of antiretroviral therapy significantly improves survival, as compared with deferred therapy.[31]

AIDS
When CD4+ T cell numbers decline below a critical level of 200 cells per L, cell-mediated immunity is lost, and infections with a variety of opportunistic microbes appear. The first symptoms often include moderate and unexplained weight loss, recurring respiratory tract infections (such as sinusitis, bronchitis, otitis media, pharyngitis), prostatitis, skin rashes, and oral ulcerations. Common opportunistic infections and tumors, most of which are normally controlled by robust CD4+ T cell-mediated immunity then start to affect the patient. Typically, resistance is lost early on to oral Candida species and to Mycobacterium tuberculosis, which leads to an increased susceptibility to oral candidiasis (thrush) and tuberculosis. Later, reactivation of latent herpes viruses may cause worsening recurrences of herpes simplex eruptions, shingles, Epstein-Barr virus-induced B-cell lymphomas, or Kaposi's sarcoma. Pneumonia caused by the fungus Pneumocystis jirovecii is common and often fatal. In the final stages of AIDS, infection with cytomegalovirus (another herpes virus) or Mycobacterium avium complex is more prominent. Not all patients with AIDS get all these infections or tumors, and there are other tumors and infections that are less prominent but still significant.

Transmission
Estimated per-act risk for acquisition of HIV by exposure route[32][33] Estimated infections Exposure Route per 10,000 exposures to an infected source [34] Blood transfusion 9,000 Childbirth 2,500[35] Needle-sharing injection drug use 67[36] Percutaneous needle stick 30[37] 170 [30890][38] / 143 [48Receptive anal intercourse (2009 and 2010 studies) 285][33] Receptive anal intercourse (based on data of a 1992 50[39][40] study) Insertive anal intercourse for uncircumcised men (2010 62a [7-168][33] study) Insertive anal intercourse for circumcised men (2010 11a [224][33] study) Insertive anal intercourse (based on data of a 1992 6.5[39][40] study) Low-income country female-to-male 38 [13110][38] Low-income country male-to-female 30 [1463][38] Receptive penile-vaginal intercourse 10[39][40][41] Insertive penile-vaginal intercourse 5[39][40] Fellating a man 1b[40] Man being fellated 0.5b[40] The data shown represents the rate of transmission when condoms were not used. Note that risk rates may change due to other factors such as commercial sex exposure, phase of HIV infection, presence or history of genital ulcers, and national income levels.[38] Bracketed values represent 95% confidence interval "best-guess estimate" Pooled transmission probability estimate a Other studies found insufficient evidence that male circumcision protects against HIV infection among men who have sex with men[42][43] b Oral trauma, sores, inflammation, concomitant sexually transmitted infections, ejaculation in the mouth, and systemic immune suppression may increase HIV transmission rate.[44] Three main transmission routes for HIV have been identified. HIV-2 is transmitted much less frequently by the mother-to-child and sexual route than HIV-1.

Sexual
The majority of HIV infections are acquired through unprotected sexual relations. Complacency about HIV plays a key role in HIV risk.[3][4] Sexual transmission can occur when infected sexual secretions of one partner come into contact with the genital, oral, or rectalmucous membranes of another. In high-income countries, the risk of female-to-male transmission is 0.04% per act and male-to-female transmission is 0.08% per act. For various reasons, these rates are 4 to 10 times higher in low-income countries.[38] The rate for receptive anal intercourse is much higher, 1.7% per act.[38] A 1999 meta-analysis of studies of condom use showed that the consistent use of latexcondoms reduces the risk of sexual transmission of HIV by about 85%.[45] However, spermicide may actually increase the transmission rate.[46][47][48] Randomized, controlled trials in which uncircumcised men were randomly assigned to be medically circumcised in sterile conditions and given counseling and other men were not circumcised have been conducted in South Africa,[49]Kenya,[50] and Uganda[51] showing reductions in female-to-male sexual HIV transmission of 60%, 53%, and 51%, respectively. As a result, a panel of experts convened by WHO and the UNAIDS Secretariat has "recommended that male circumcision now be recognized as an additional important intervention to reduce the risk of heterosexually acquired HIV infection in men."[52] Among men who have sex with men, there is insufficient evidence that male circumcision protects against HIV infection or other Sexually Transmitted Infections.[42] Studies of HIV among women having undergone female genital cutting (FGC) have reported mixed results, but with some evidence of increased risk of transmission.[53][54][55][56]Programmes that aim to encourage sexual abstinence while also encouraging and teaching safer sex strategies for those who are sexually active can reduce short- and long-term HIV risk behaviour among young people in high-income countries, according to a 2007 Cochrane Review of studies.[57]

Blood products
In general, if infected blood comes into contact with any open wound, HIV may be transmitted. This transmission route can account for infections in intravenous drug users, hemophiliacs, and recipients of blood transfusions (though most transfusions are checked for HIV in the developed world) and blood products. It is also of concern for persons receiving medical care in regions where there is prevalent substandard hygiene in the use of injection equipment, such as the reuse of needles in Third World countries. Health care workers such as nurses, laboratory workers, and doctors have also been infected, although this occurs more rarely. Since transmission of HIV by blood became known medical personnel are required to protect themselves from contact with blood by the use of universal precautions. People giving and receiving tattoos, piercings, and scarification procedures can also be at risk of infection.

HIV has been found at low concentrations in the saliva, tears, and urine of infected individuals, but there are no recorded cases of infection by these secretions and the potential risk of transmission is negligible.[58] It is not possible for mosquitoes to transmit HIV.[59]

Mother-to-child
The transmission of the virus from the mother to the child can occur in utero (during pregnancy), intrapartum (at childbirth), or via breast feeding. In the absence of treatment, the transmission rate up to birth between the mother and child is around 25%.[35] However, where combination antiretroviral drug treatment and Cesarian section are available, this risk can be reduced to as low as one percent.[35] Postnatal mother-to-child transmission may be largely prevented by complete avoidance of breast feeding; however, this has significant associated morbidity. Exclusive breast feeding and the provision of extended antiretroviral prophylaxis to the infant are also efficacious in avoiding transmission.[60] UNAIDS estimate that 430,000 children were infected worldwide in 2008 (19% of all new infections), primarily by this route, and that a further 65,000 infections were averted through the provision of antiretroviral prophylaxis to HIV-positive women.[61]

Multiple infection
Unlike some other viruses, infection with HIV does not provide immunity against additional infections, in particular, in the case of more genetically distant viruses. Both inter- and intraclade multiple infections have been reported,[62] and even associated with more rapid disease progression.[63] Multiple infections are divided into two categories depending on the timing of the acquisition of the second strain. Coinfection refers to two strains that appear to have been acquired at the same time (or too close to distinguish). Reinfection (or superinfection) is infection with a second strain at a measurable time after the first. Both forms of dual infection have been reported for HIV in both acute and chronic infection around the world.[64][65][66][67]

Prevention
There is currently no publicly available vaccine for HIV or AIDS.[68][69][70] However, a vaccine that is a combination of two previously unsuccessful vaccine candidates (ALVACHIV and AIDSVAX) was reported in September 2009 to have resulted in a 30% reduction in infections in a trial conducted in Thailand.[71][72] Further trials of the vaccine are ongoing.[73][74] Additionally, a course of antiretroviral treatment administered immediately after exposure, referred to as post-exposure prophylaxis, is believed to reduce the risk of infection if begun as quickly as possible.[75] In July 2010, a vaginal gel containing tenofovir, a reverse transcriptase inhibitor, was shown to reduce HIV infection rates by 39 percent in a trial conducted in South Africa.[76] Early treatment of HIV-infected people with antiretrovirals protected 96% of partners from infection.[77]

Virology
Structure and genome

Human immunodeficiency virus

Scanning electron micrograph of HIV-1 (in green) budding from cultured lymphocyte. Multiple round bumps on cell surface represent sites of assembly and budding of virions.

Virus classification Group VI (ssRNART)

Group:

Family: Retroviridae Genus: Lentivirus Species

y

Human immunodeficiency virus 1

Human immunodeficiency virus 2

HIV is different in structure from other retroviruses. It is roughly spherical[78] with a diameter of about 120 nm, around 60 times smaller than a red blood cell, yet large for a virus.[79] It is composed of two copies of positive single-stranded RNA that codes for the virus's nine genes enclosed by a conical capsid composed of 2,000 copies of the viral protein p24.[80] The single-stranded RNA is tightly bound to nucleocapsid proteins, p7, and enzymes needed for the development of the virion such as reverse transcriptase, proteases, ribonuclease and integrase. A matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle.[80] This is, in turn, surrounded by the viral envelope that is composed of two layers of fatty molecules called phospholipids taken from the membrane of a human cell when a newly formed virus particle buds from the cell. Embedded in the viral envelope are proteins from the host cell and about 70 copies of a complex HIV protein that protrudes through the surface of the virus particle.[80] This protein, known as Env, consists of a cap made of three molecules called glycoprotein (gp) 120, and a stem consisting of three gp41 molecules that anchor the structure into the viral envelope.[81] This glycoprotein complex enables the virus to attach to and fuse with target cells to initiate the infectious cycle.[81] Both these surface proteins, especially gp120, have been considered as targets of future treatments or vaccines against HIV.[82] The RNA genome consists of at least seven structural landmarks (LTR, TAR, RRE, PE, SLIP, CRS, and INS), and nine genes (gag, pol, and env, tat, rev, nef, vif, vpr, vpu, and sometimes a tenth tev, which is a fusion of tat env and rev), encoding 19 proteins. Three of these genes, gag, pol, and env, contain information needed to make the structural proteins for new virus particles.[80] For example, env codes for a protein called gp160 that is broken down by a viral enzyme to form gp120 and gp41. The six remaining genes, tat, rev, nef, vif, vpr, and vpu (or vpx in the case of HIV-2), are regulatory genes for proteins that control the ability of HIV to infect cells, produce new copies of virus (replicate), or cause disease.[80] The two Tat proteins (p16 and p14) are transcriptional transactivators for the LTR promoter acting by binding the TAR RNA element. The TAR may also be processed into microRNAs that regulate the apoptosis genes ERCC1 and IER3.[83][84] The Rev protein (p19) is involved in shuttling RNAs from the nucleus and the cytoplasm by binding to the RRE RNA element. The Vif protein (p23) prevents the action of APOBEC3G (a cell protein that deaminates DNA:RNA hybrids and/or interferes with the Pol protein). The Vpr protein (p14) arrests cell division at G2/M. The Nef protein (p27) down-regulates CD4 (the major viral receptor), as well as the MHC class I and class II molecules.[85][86][87] Nef also interacts with SH3 domains. The Vpu protein (p16) influences the release of new virus particles from infected cells.[80] The ends of each strand of HIV RNA contain an RNA

sequence called the long terminal repeat (LTR). Regions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell. The Psi element is involved in viral genome packaging and recognized by Gag and Rev proteins. The SLIP element (TTTTTT) is involved in the frameshift in the Gag-Pol reading frame required to make functional Pol.[80]

Tropism
Main article: HIV tropism

Diagram of the immature and mature forms of HIV The term viral tropism refers to which cell types HIV infects. HIV can infect a variety of immune cells such as CD4+ T cells, macrophages, and microglial cells. HIV-1 entry to macrophages and CD4+ T cells is mediated through interaction of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells and also with chemokinecoreceptors.[81] Macrophage (M-tropic) strains of HIV-1, or non-syncitia-inducing strains (NSI) use the chemokine receptor CCR5 for entry and are, thus, able to replicate in macrophages and

CD4+T cells.[88] This CCR5 coreceptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype. Indeed, macrophages play a key role in several critical aspects of HIV infection. They appear to be the first cells infected by HIV and perhaps the source of HIV production when CD4+ cells become depleted in the patient. Macrophages and microglial cells are the cells infected by HIV in the central nervous system. In tonsils and adenoids of HIV-infected patients, macrophages fuse into multinucleated giant cells that produce huge amounts of virus. T-tropic isolates, or syncitia-inducing (SI) strains replicate in primary CD4+ T cells as well as in macrophages and use the -chemokine receptor, CXCR4, for entry.[88][89][90] Dual-tropic HIV-1 strains are thought to be transitional strains of HIV-1 and thus are able to use both CCR5 and CXCR4 as co-receptors for viral entry. The -chemokine SDF-1, a ligand for CXCR4, suppresses replication of T-tropic HIV-1 isolates. It does this by down-regulating the expression of CXCR4 on the surface of these cells. HIV that use only the CCR5 receptor are termed R5; those that use only CXCR4 are termed X4, and those that use both, X4R5. However, the use of coreceptor alone does not explain viral tropism, as not all R5 viruses are able to use CCR5 on macrophages for a productive infection[88] and HIV can also infect a subtype of myeloid dendritic cells,[91] which probably constitute a reservoir that maintains infection when CD4+ T cell numbers have declined to extremely low levels. Some people are resistant to certain strains of HIV.[92] For example, people with the CCR532 mutation are resistant to infection with R5 virus, as the mutation stops HIV from binding to this coreceptor, reducing its ability to infect target cells. Sexual intercourse is the major mode of HIV transmission. Both X4 and R5 HIV are present in the seminal fluid, which is passed from a male to his sexual partner. The virions can then infect numerous cellular targets and disseminate into the whole organism. However, a selection process leads to a predominant transmission of the R5 virus through this pathway.[93][94][95] How this selective process works is still under investigation, but one model is that spermatozoa may selectively carry R5 HIV as they possess both CCR3 and CCR5 but not CXCR4 on their surface[96] and that genital epithelial cells preferentially sequester X4 virus.[97] In patients infected with subtype B HIV-1, there is often a co-receptor switch in late-stage disease and T-tropic variants appear that can infect a variety of T cells through CXCR4.[98] These variants then replicate more aggressively with heightened virulence that causes rapid T cell depletion, immune system collapse, and opportunistic infections that mark the advent of AIDS.[99] Thus, during the course of infection, viral adaptation to the use of CXCR4 instead of CCR5 may be a key step in the progression to AIDS. A number of studies with subtype B-infected individuals have determined that between 40 and 50% of AIDS patients can harbour viruses of the SI and, it is presumed, the X4 phenotypes.[100][101] HIV-2 is much less pathogenic than HIV-1 and is restricted in its worldwide distribution. The adoption of "accessory genes" by HIV-2 and its more promiscuous pattern of coreceptor usage (including CD4-independence) may assist the virus in its adaptation to avoid innate restriction factors present in host cells. Adaptation to use normal cellular machinery to

enable transmission and productive infection has also aided the establishment of HIV-2 replication in humans. A survival strategy for any infectious agent is not to kill its host but ultimately become a commensal organism. Having achieved a low pathogenicity, over time, variants more successful at transmission will be selected.[102]

Replication cycle

The HIV replication cycle Entry to the cell HIV enters macrophages and CD4+T cells by the adsorption of glycoproteins on its surface to receptors on the target cell followed by fusion of the viral envelope with the cell membrane and the release of the HIV capsid into the cell.[103][104]

Entry to the cell begins through interaction of the trimeric envelope complex (gp160 spike) and both CD4 and a chemokine receptor (generally either CCR5 or CXCR4, but others are known to interact) on the cell surface.[103][104] gp120 binds to integrin 4 7 activating LFA-1 the central integrin involved in the establishment of virological synapses, which facilitate efficient cell-to-cell spreading of HIV-1.[105]The gp160 spike contains binding domains for both CD4 and chemokine receptors.[103][104] The first step in fusion involves the high-affinity attachment of the CD4 binding domains of gp120 to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine binding domains of gp120 and allowing them to interact with the target chemokine receptor.[103][104] This allows for a more stable twopronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane.[103][104] Repeat sequences in gp41, HR1, and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.[103][104] After HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease, and protease, are injected into the cell.[103]During the microtubule-based transport to the nucleus, the viral single-strand RNA genome is transcribed into double-strand DNA, which is then integrated into a host chromosome. HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but another route using mannose-specific C-type lectin receptors such as DC-SIGN can also be used.[106] DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T-cells when the virus is captured in the mucosa by DCs.[106]The presence of FEZ-1, which occurs naturally in neurons, is believed to prevent the infection of cells by HIV.[107] Replication and transcription Shortly after the viral capsid enters the cell, an enzyme called reverse transcriptase liberates the single-stranded (+)RNA genome from the attached viral proteins and copies it into a complementary DNA (cDNA) molecule.[108]The process of reverse transcription is extremely error-prone, and the resulting mutations may cause drug resistance or allow the virus to evade the body's immune system. The reverse transcriptase also has ribonuclease activity that degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent DNA polymerase activity that creates a sense DNA from the antisensecDNA.[109] Together, the cDNA and its complement form a double-stranded viral DNA that is then transported into the cell nucleus. The integration of the viral DNA into the host cell's genome is carried out by another viral enzyme called integrase.[108]

Reverse transcription of the HIV genome into double strand DNA This integrated viral DNA may then lie dormant, in the latent stage of HIV infection.[108]To actively produce the virus, certain cellular transcription factors need to be present, the most important of which is NF- B (NF kappa B), which is upregulated when T-cells become activated.[110]This means that those cells most likely to be killed by HIV are those currently fighting infection. During viral replication, the integrated DNA provirus is transcribed into mRNA, which is then spliced into smaller pieces. These small pieces are exported from the nucleus into the cytoplasm, where they are translated into the regulatory proteins Tat (which encourages new virus production) and Rev. As the newly produced Rev protein accumulates in the nucleus, it binds to viral mRNAs and allows unspliced RNAs to leave the nucleus, where they are otherwise retained until spliced.[111]At this stage, the structural proteins Gag and Env are produced from the full-length mRNA. The full-length RNA is actually the virus genome; it binds to the Gag protein and is packaged into new virus particles.

HIV-1 and HIV-2 appear to package their RNA differently; HIV-1 will bind to any appropriate RNA, whereas HIV-2 will preferentially bind to the mRNA that was used to create the Gag protein itself. This may mean that HIV-1 is better able to mutate (HIV-1 infection progresses to AIDS faster than HIV-2 infection and is responsible for the majority of global infections). Assembly and release The final step of the viral cycle, assembly of new HIV-1 virons, begins at the plasma membrane of the host cell. The Envpolyprotein (gp160) goes through the endoplasmic reticulum and is transported to the Golgi complex where it is cleaved by protease and processed into the two HIV envelope glycoproteins gp41 and gp120. These are transported to the plasma membrane of the host cell where gp41 anchors the gp120 to the membrane of the infected cell. The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell. Maturation occurs either in the forming bud or in the immature virion after it buds from the host cell. During maturation, HIV proteases cleave the polyproteins into individual functional HIV proteins and enzymes. The various structural components then assemble to produce a mature HIV virion.[112]This cleavage step can be inhibited by protease inhibitors. The mature virus is then able to infect another cell.

Genetic variability

The phylogenetic tree of the SIV and HIV.

HIV differs from many viruses in that it has very high genetic variability. This diversity is a result of its fast replication cycle, with the generation of about 1010virions every day, coupled with a high mutation rate of approximately 3 x 105 per nucleotide base per cycle of replication and recombinogenic properties of reverse transcriptase.[113][114][115] This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day.[113]This variability is compounded when a single cell is simultaneously infected by two or more different strains of HIV. When simultaneous infection occurs, the genome of progeny virions may be composed of RNA strands from two different strains. This hybrid virion then infects a new cell where it undergoes replication. As this happens, the reverse transcriptase, by jumping back and forth between the two different RNA templates, will generate a newly synthesized retroviral DNA sequence that is a recombinant between the two parental genomes.[113]This recombination is most obvious when it occurs between subtypes.[113] The closely related simian immunodeficiency virus (SIV) has evolved into many strains, classified by the natural host species. SIV strains of the African green monkey (SIVagm) and sooty mangabey (SIVsmm) are thought to have a long evolutionary history with their hosts. These hosts have adapted to the presence of the virus,[116] which is present at high levels in the host's blood but evokes only a mild immune response,[117] does not cause the development of simian AIDS,[118] and does not undergo the extensive mutation and recombination typical of HIV infection in humans.[119] In contrast, when these strains infect species that have not adapted to SIV ("heterologous" hosts such as rhesus or cynomologus macaques), the animals develop AIDS and the virus generates genetic diversity similar to what is seen in human HIV infection.[120] Chimpanzee SIV (SIVcpz), the closest genetic relative of HIV-1, is associated with increased mortality and AIDS-like symptoms in its natural host.[121] Both SIVcpz and HIV-1 appear to have been transmitted relatively recently to chimpanzee and human populations, so their hosts have not yet adapted to the virus.[116] Both viruses have also lost a function of the Nef gene that is present in most SIVs; without this function, T cell depletion is more likely, leading to immunodeficiency.[121] Three groups of HIV-1 have been identified on the basis of differences in the envelope (env) region: M, N, and O.[122] Group M is the most prevalent and is subdivided into eight subtypes (or clades), based on the whole genome, which are geographically distinct.[123]The most prevalent are subtypes B (found mainly in North America and Europe), A and D (found mainly in Africa), and C (found mainly in Africa and Asia); these subtypes form branches in the phylogenetic tree representing the lineage of the M group of HIV-1. Coinfection with distinct subtypes gives rise to circulating recombinant forms (CRFs). In 2000, the last year in which an analysis of global subtype prevalence was made, 47.2% of infections worldwide were of subtype C, 26.7% were of subtype A/CRF02_AG, 12.3% were of subtype B, 5.3% were of subtype D, 3.2% were of CRF_AE, and the remaining 5.3% were composed of other subtypes and CRFs.[124] Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes.[125]The existence of a fourth group, "P", has been hypothesised based

on a virus isolated in 2009.[126][127][128] The strain is apparently derived from gorilla SIV (SIVgor), first isolated from western lowland gorillas in 2006.[126] The genetic sequence of HIV-2 is only partially homologous to HIV-1 and more closely resembles that of SIVsmm.

Diagnosis
Many HIV-positive people are unaware that they are infected with the virus.[129] For example, less than 1% of the sexually active urban population in Africa have been tested and this proportion is even lower in rural populations.[129]Furthermore, only 0.5% of pregnant women attending urban health facilities are counselled, tested or receive their test results.[129] Again, this proportion is even lower in rural health facilities.[129]Since donors may therefore be unaware of their infection, donor blood and blood products used in medicine and medical research are routinely screened for HIV.[130] HIV-1 testing consists of initial screening with an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to HIV-1. Specimens with a nonreactive result from the initial ELISA are considered HIV-negative unless new exposure to an infected partner or partner of unknown HIV status has occurred. Specimens with a reactive ELISA result are retested in duplicate.[131]If the result of either duplicate test is reactive, the specimen is reported as repeatedly reactive and undergoes confirmatory testing with a more specific supplemental test (e.g., Western blot or, less commonly, an immunofluorescence assay (IFA)). Only specimens that are repeatedly reactive by ELISA and positive by IFA or reactive by Western blot are considered HIV-positive and indicative of HIV infection. Specimens that are repeatedly ELISA-reactive occasionally provide an indeterminate Western blot result, which may be either an incomplete antibody response to HIV in an infected person or nonspecific reactions in an uninfected person.[132] Although IFA can be used to confirm infection in these ambiguous cases, this assay is not widely used. In general, a second specimen should be collected more than a month later and retested for persons with indeterminate Western blot results. Although much less commonly available, nucleic acid testing (e.g., viral RNA or proviral DNA amplification method) can also help diagnosis in certain situations.[131] In addition, a few tested specimens might provide inconclusive results because of a low quantity specimen. In these situations, a second specimen is collected and tested for HIV infection. Modern HIV testing is extremely accurate. The chance of a false-positive result in the twostep testing protocol is estimated to be 0.0004% to 0.0007% in the general U.S. population.[133][134][135][136]

Screening
President of South Africa, Jacob Zuma is launching HIV testing for secondary schools in March 2011 on weekends and holidays. The government believes that knowing HIV status

could allow early access to life-saving treatment and help prevent the spread of the infection. But critics warn of psychological harm for young people from positive test results.[137]

Treatment

Abacavir a nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs) There is currently no cure for HIV infection. Treatment consists of highly active antiretroviral therapy, or HAART.[138]This has been highly beneficial to many HIV-infected individuals since its introduction in 1996, when the protease inhibitor-based HAART initially became available.[139] Current HAART options are combinations (or "cocktails") consisting of at least three drugs belonging to at least two types, or "classes," of antiretroviral agents. Typically, these classes are two nucleoside analogue reverse transcriptase inhibitors (NARTIs or NRTIs) plus either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI). There is no empirical evidence for withholding treatment at any stage of HIV infection,[140] and death rates are almost twice as high when therapy is deferred (until the CD4 count falls below 500) compared to starting therapy when the CD4 count is above 500.[31] However, the timing for starting HIV treatment is still subject to debate.[141] The United States Panel on Antiretroviral Guidelines for Adults and Adolescents in 2009 recommended that antiretroviral therapy should be initiated in all patients with a CD4 count less than 350, with treatment also recommended for patients with CD4 counts between 350 and 500. However, for patients with CD4 counts over 500, the expert Panel was evenly divided, with 50% in favor of starting antiretroviral therapy at this stage of HIV disease, and 50% viewing initiating therapy at this stage as optional. They noted that "Patients initiating antiretroviral therapy should be willing and able to commit to lifelong treatment and should understand the benefits and risks of therapy and the importance of adherence".[142] New classes of drugs such as entry inhibitors provide treatment options for patients infected with viruses already resistant to common therapies, although they are not widely available and not typically accessible in resource-limited settings. Because AIDS progression in

children is more rapid and less predictable than in adults, in particular, in young infants, more aggressive treatment is recommended for children than adults.[143]In developed countries where HAART is available, doctors assess their patients thoroughly: measuring the viral load, how fast CD4 declines, and patient readiness. They then decide when to recommend starting treatment.[144] HAART neither cures the patient nor uniformly removes all symptoms; high levels of HIV1, often HAART-resistant, return if treatment is stopped.[145][146] Moreover, it would take more than a lifetime for HIV infection to be cleared using HAART.[147] Despite this, many HIV-infected individuals have experienced remarkable improvements in their general health and quality of life, which has led to a large reduction in HIV-associated morbidity and mortality in the developed world.[139][148][149] One study suggests the average life expectancy of an HIV infected individual is 32 years from the time of infection if treatment is started when the CD4 count is 350/L.[150] Life expectancy is further enhanced if antiretroviral therapy is initiated before the CD4 count falls below 500/L.[31] In the absence of HAART, progression from HIV infection to AIDS has been observed to occur at a median of between nine to ten years and the median survival time after developing AIDS is only 9.2 months.[16] However, HAART sometimes achieves far less than optimal results, in some circumstances being effective in less than fifty percent of patients.[citation needed] This is due to a variety of reasons such as medication intolerance/side effects, prior ineffective antiretroviral therapy and infection with a drug-resistant strain of HIV. However, non-adherence and non-persistence with antiretroviral therapy is the major reason most individuals fail to benefit from HAART.[151] The reasons for non-adherence and non-persistence with HAART are varied and overlapping. Major psychosocial issues, such as poor access to medical care, inadequate social supports, psychiatric disease and drug abuse contribute to non-adherence. The complexity of these HAART regimens, whether due to pill number, dosing frequency, meal restrictions or other issues along with side effects that create intentional non-adherence also contribute to this problem.[152][153][154] The side effects include lipodystrophy, dyslipidemia, insulin resistance, an increase in cardiovascular risks, and birth defects.[155][156] Anti-retroviral drugs are expensive, and the majority of the world's infected individuals do not have access to medications and treatments for HIV and AIDS.[157] Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance. Unfortunately, only a vaccine is thought to be able to halt the pandemic. This is because a vaccine would cost less, thus being affordable for developing countries, and would not require daily treatment.[157] However, after over 20 years of research, HIV-1 remains a difficult target for a vaccine.[157]

HIV latent reservoir

Despite the success of highly active antiretroviral therapy (HAART) in controlling HIV infection and reducing HIV-associated mortality, current drug regimens are unable to

completely eradicate HIV infection. Many people on HAART achieve suppression of HIV to levels below the limit of detection of standard clinical assays for many years. However, upon withdrawal of HAART, HIV viral loads rebound quickly with a concomitant decline in CD4+T-Cells, which, in most cases, without a resumption of treatment, leads to AIDS. To successfully reproduce itself, HIV must convert its RNA genome to DNA, which is then imported into the host cell's nucleus and inserted into the host genome through the action of HIV integrase. Because HIV's primary cellular target, CD4+ T-Cells, function as the memory cells of the immune system, integrated HIV can remain dormant for the duration of these cells' lifetime. Memory T-Cells may survive for many years and possibly for decades. The latent HIV reservoir can be measured by co-culturing CD4+ T-Cells from infected patients with CD4+ T-Cells from uninfected donors and measuring HIV protein or RNA.[158] The failure of vaccine candidates to protect against HIV infection and progression to AIDS has led to a renewed focus on the biological mechanisms responsible for HIV latency. A limited period of therapy combining anti-retrovirals with drugs targeting the latent reservoir may one day allow for total eradication of HIV infection.[159]

Prognosis
Without treatment, the net median survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype,[160] and the median survival rate after diagnosis of AIDS in resource-limited settings where treatment is not available ranges between 6 and 19 months, depending on the study.[161] In areas where it is widely available, the development of HAART as effective therapy for HIV infection and AIDS reduced the death rate from this disease by 80%, and raised the life expectancy for a newly diagnosed HIVinfected person to 2050 years.[162][163] As new treatments continue to be developed and because HIV continues to evolve resistance to treatments, estimates of survival time are likely to continue to change. Without antiretroviral therapy, death normally occurs within a year after the individual progresses to AIDS.[16] Most patients die from opportunistic infections or malignancies associated with the progressive failure of the immune system.[12] The rate of clinical disease progression varies widely between individuals and has been shown to be affected by many factors such as host susceptibility and immune function[92][164][165] health care and co-infections,[12][16] as well as which particular strain of the virus is involved.[166][167][168]

Epidemiology

Estimated prevalence of HIV among young adults (1549) per country at the end of 2005.

Numbers of people living with, newly infected with, and killed by HIV (19902008)[169]

UNAIDS and the WHO estimated that AIDS killed more than 25 million people between 1981, when it was first recognized, and 2005, making it one of the most destructive pandemics in recorded history. Despite improved access to antiretroviral treatment and care in many regions of the world, the AIDS pandemic claimed an estimated 2.8 million (between 2.4 and 3.3 million) lives in 2005 of which more than half a million (570,000) were children.[5] UNAIDS estimated that 33.3 million people were living with HIV at the end of 2009, up from 26.2 million people in 1999. They also estimated AIDS-related deaths in 2009 at 1.8 million people, down from a peak of 2.1 million in 2004, new infections at 2.6 million, down from a peak of 3.2 million in 1997, and the number of people in low- or middleincome countries receiving antiretroviral therapy in 2009 at 5.2 million, up from 4.0 million in 2008.[6] Sub-Saharan Africa remains by far the worst-affected region, with an estimated 22.5 million people currently living with HIV (67% of the global total), 1.3 million deaths (72% of the global total) and 1.8 million new infections (69% of the global total). However, the number of new infections declined by 19% across the region between 2001 and 2009, and by more than 25% in 22 sub-Saharan African countries during this period. Asia is the second-worst affected region, with 4.9 million people living with HIV (15% of the global total).[6] The latest evaluation report of the World Bank's Operations Evaluation Department assesses the development effectiveness of the World Bank's country-level HIV/AIDS assistance defined as policy dialogue, analytic work, and lending with the explicit objective of reducing the scope or impact of the AIDS epidemic.[170]This is the first comprehensive evaluation of the World Bank's HIV/AIDS support to countries, from the beginning of the epidemic through mid-2004. Because the Bank aims to assist in implementation of national government programmes, their experience provides important insights on how national AIDS programmes can be made more effective. The development of HAART as effective therapy for HIV infection has substantially reduced the death rate from this disease in those areas where these drugs are widely available.[139]As the life expectancy of persons with HIV has increased in countries where HAART is widely used, the continuing spread of the disease has caused the number of persons living with HIV to increase substantially. In Africa, the number of mother-to-child-transmission (MTCT) cases and the prevalence of AIDS is beginning to reverse decades of steady progress in child survival. Countries such as Uganda are attempting to curb the MTCT epidemic by offering VCT (voluntary counselling and testing), PMTCT (prevention of mother-to-child transmission) and ANC (ante-natal care) services, which include the distribution of antiretroviral therapy.

History
Origins

HIV is thought to have originated in non-human primates in sub-Saharan Africa and was transferred to humans late in the 19th or early in the 20th century.[171][172][173] The first paper recognizing a pattern of opportunistic infections characteristic of AIDS was published in 1981.[174] Both HIV-1 and HIV-2 are believed to have originated in West-Central Africa and to have jumped species (a process known as zoonosis) from non-human primates to humans. HIV-1 appears to have originated in southern Cameroon through the evolution of SIV(cpz), a simian immunodeficiency virus (SIV) that infects wild chimpanzees (HIV-1 descends from the SIVcpz endemic in the chimpanzee subspecies Pan troglodytes troglodytes).[175][176] The closest relative of HIV-2 is SIV(smm), a virus of the sooty mangabey (Cercocebusatysatys), an Old World monkey living in litoral West Africa (from southern Senegal to western Ivory Coast.[22]New World monkeys such as the owl monkey are resistant to HIV-1 infection, possibly because of a genomic fusion of two viral resistance genes.[177] There is evidence that humans who participate in bushmeat activities, either as hunters or as bushmeat vendors, commonly acquire SIV.[178]However, only a few of these infections were able to cause epidemics in humans, and all did so in the late 19thearly 20th century. To explain why HIV became epidemic only by that time, there are several theories, each invoking specific driving factors that may have promoted SIV adaptation to humans, or initial spread: social changes following colonialism,[179] rapid transmission of SIV through unsafe or unsterile injections (that is, injections in which the needle is reused without being sterilised),[180] colonial abuses and unsafe smallpox vaccinations or injections,[181] or prostitution and the concomitant high frequency of genital ulcer diseases (such as syphilis) in nascent colonial cities[182][183]

Discovery
AIDS was first clinically observed between late 1980 and early 1981.[184] Injection drug users and gay men with no known cause of impaired immunity showed symptoms of Pneumocystis carinii pneumonia (PCP), a rare opportunistic infection that was known to present itself in people with very compromised immune systems.[185][186][187] Soon thereafter, additional gay men developed a previously-rare skin cancer called Kaposis sarcoma (KS).[188][189] Many more cases of PCP and KS quickly emerged, alerting U.S. Centers for Disease Control and Prevention (CDC). A CDC task force was formed to monitor the outbreak. After recognizing a pattern of anomalous symptoms presenting themselves in patients, the task force named the condition acquired immune deficiency syndrome (AIDS).[190] In 1983, two separate research groups led by Robert Gallo and Luc Montagnier independently declared that a novel retrovirus may have been infecting AIDS patients, and published their findings in the same issue of the journal Science.[191][192] Gallo claimed that a virus his group had isolated from an AIDS patient was strikingly similar in shape to other human T-lymphotropic viruses (HTLVs) his group had been the first to isolate. Gallo's group called their newly isolated virus HTLV-III. At the same time,

Montagnier's group isolated a virus from a patient presenting lymphadenopathy (swelling of the lymph nodes) of the neck and physical weakness, two classic symptoms of AIDS. Contradicting the report from Gallo's group, Montagnier and his colleagues showed that core proteins of this virus were immunologically different from those of HTLV-I. Montagnier's group named their isolated virus lymphadenopathy-associated virus (LAV).[190] HIV was chosen as a compromise between the two claims (LAV and HTLVIII). Whether Gallo or Montagnier deserve more credit for the discovery of the virus that causes AIDS has been a matter of considerable controversy. Together with his colleague Franoise Barr-Sinoussi, Montagnier was awarded one half of the 2008 Nobel Prize in Physiology or Medicine for his "discovery of human immunodeficiency virus".[193]HaraldzurHausen also shared the Prize for his discovery that human papilloma virus leads to cervical cancer, but Gallo was left out.[194] Gallo said that it was "a disappointment" that he was not named a co-recipient.[195]Montagnier said he was "surprised" Gallo was not recognized by the Nobel Committee: "It was important to prove that HIV was the cause of AIDS, and Gallo had a very important role in that. I'm very sorry for Robert Gallo."[194]

AIDS denialism
A small group of individuals continue to dispute the connection between HIV and AIDS,[196] the existence of HIV itself, or the validity of HIV testing and treatment methods.[197][198] These claims, known as AIDS denialism, have been examined and rejected by the scientific community.[199] However, they have had a significant political impact, particularly in South Africa, where the government's official embrace of AIDS denialism was responsible for its ineffective response to that country's AIDS epidemic, and has been blamed for hundreds of thousands of avoidable deaths and HIV infections.[200][201][202]

Research
Stem cell transplantation
In 2007, a 40-year-old HIV-positive man was given a stem cell transplant as part of his treatment for acute myelogenous leukemia (AML).[203] A second transplant was made a year later after a relapse. The donor was chosen not only for genetic compatibility but also for being homozygous for a CCR5- 32 mutation that confers resistance to HIV infection.[204][205] After 20 months without antiretroviral drug treatment, it was reported that HIV levels in the recipient's blood, bone marrow, and bowel were below the limit of detection.[205] Virus remained undetectable over three years after the first transplant.[203] Although the researchers and some commentators have characterized this result as a cure, others suggest that the virus may remain hidden in tissues[206] such as the brain (a viral reservoir).[207]Stem cell treatment remains investigational because of its

anecdotalnature, the disease and mortality risk associated with stem cell transplants, and the difficulty of finding suitable donors.[206][208]

Immunomodulatory agents
Complementing efforts to control viral replication, immunotherapies that may assist in the recovery of the immune system have been explored in past and ongoing trials, including IL-2 and IL-7.[

Influenza A virus subtype H1N1

Influenza (Flu)

Types

Avian (A/H5N1 subtype) Canine Equine Swine (A/H1N1 subtype)

Vaccines

2009 pandemic (Pandemrix) ACAM-FLU-A Fluzone Influvac Live attenuated (FluMist) Optaflu

Treatment

Amantadine Arbidol Laninamivir Oseltamivir Peramivir Rimantadine Vitamin D Zanamivir

Pandemics

2009 Swine 19681969 Hong Kong 1918

Outbreaks

2008 West Bengal 2007 Bernard Matthews H5N1 2007 Australian equine 2006 H5N1 India 1976 swine flu

See also

Flu season Influenza evolution Influenza research Influenza-like illness

vde

Influenza A (H1N1) virus is a subtype of influenza A virus and was the most common cause of human influenza (flu) in 2009. Some strains of H1N1 are endemic in humans and cause a small fraction of all influenza-like illness and a small fraction of all seasonal influenza. H1N1 strains caused a few percent of all human flu infections in 20042005.[1] Other strains of H1N1 are endemic in pigs (swine influenza) and in birds (avian influenza). In June 2009, the World Health Organization declared the new strain of swine-origin H1N1 as a pandemic. This strain is often called swine flu by the public media. This novel virus spread worldwide and had caused about 17,000 deaths by the start of 2010. On August 10, 2010, the World Health Organization declared the H1N1 influenza pandemic over, saying worldwide flu activity had returned to typical seasonal patterns.[2] As of 26 April 2011, an H1N1 pandemic preparedness alert has been issued by the World Health Organisation (WHO) for the Americas. See Recombinomics- H1N1 WHO Alert 2011. The affected areas have included the Chihuahua region of Mexico where its severity and work load have been high. It is reported by the aforementioned Recombinomics source that the current vaccine (California/7/2009) for H1N1 influenza might be losing its effectiveness in 2011. This point is all the more significant since it is the current virus target for the northern hemisphere's flu vaccine, and is the intended choice for the southern hemisphere.

Swine influenza

Swine influenza (also called swine flu, or pig flu) is an infection by any one of several types of swine influenza virus. Swine influenza virus (SIV) is any strain of the influenza family of viruses that is endemic in pigs. As of 2009, the known SIV strains include influenza C and the subtypes of influenza A known as H1N1, H1N2, H3N1, H3N2, and H2N3. Swine influenza virus is common throughout pig populations worldwide. Transmission of the virus from pigs to humans is not common and does not always lead to human influenza, often resulting only in the production of antibodies in the blood. If transmission does cause human influenza, it is called zoonotic swine flu. People with regular exposure to pigs are at increased risk of swine flu infection. The meat of an infected animal poses no risk of infection when properly cooked. Pigs experimentally infected with the strain of swine flu that is causing the current human pandemic showed clinical signs of flu within four days, and the virus spread to other uninfected pigs housed with the infected ones.[3] During the mid-20th century, identification of influenza subtypes became possible, allowing accurate diagnosis of transmission to humans. Since then, only 50 such transmissions have been confirmed. These strains of swine flu rarely pass from human to human. Symptoms of zoonotic swine flu in humans are similar to those of influenza and of influenza-like illness in general, namely chills, fever, sore throat, muscle pains, severe headache, coughing, weakness and general discomfort. The recommended time of isolation is about five days.

Notable incidents
Spanish flu
The Spanish flu, also known as la grippe,La Gripa Espaola, or La Pesadilla, was an unusually severe and deadly strain of avian influenza, a viralinfectiousdisease, that killed some 50 to 100 million people worldwide over about a year in 1918 and 1919. It is thought to be one of the most deadly pandemics in human history. The 1918 flu caused an unusual number of deaths, possibly due to it causing a cytokine storm in the body.[4][5] (The current H5N1bird flu, also an Influenza A virus, has a similar effect.)[6] The Spanish flu virus infected lung cells, leading to overstimulation of the immune system via release of cytokines into the lung tissue. This leads to extensive leukocyte migration towards the lungs, causing destruction of lung tissue and secretion of liquid into the organ. This makes it difficult for the patient to breathe. In contrast to other pandemics, which mostly kill the old and the very young, the 1918 pandemic killed unusual numbers of young adults, which may have been due to their healthy immune systems mounting a too-strong and damaging response to the infection.[7] The term "Spanish" flu was coined because Spain was at the time the only European country where the press were printing reports of the outbreak, which had killed thousands in the armies fighting World War I. Other countries suppressed the news in order to protect morale.[8]

Fort Dix outbreak

In 1976, a novel swine influenza A (H1N1) caused severe respiratory illness in 13 soldiers with 1 death at Fort Dix, New Jersey. The virus was detected only from January 19 to February 9 and did not spread beyond Fort Dix.[9] Retrospective serologic testing subsequently demonstrated that up to 230 soldiers had been infected with the novel virus, which was an H1N1 strain. The cause of the outbreak is still unknown and no exposure to pigs was identified. [10]

Russian flu
The 19771978 Russian flu epidemic was caused by strain Influenza A/USSR/90/77 (H1N1). It infected mostly children and young adults under 23 because a similar strain was prevalent in 194757, causing most adults to have substantial immunity. The virus was included in the 1978 1979 influenza vaccine.[11][12][13][14]

2009 A(H1N1) pandemic

Illustration of influenza antigenic shift.

In the 2009 flu pandemic, the virus isolated from patients in the United States was found to be made up of genetic elements from four different flu viruses North American swine influenza, North American avian influenza, human influenza, and swine influenza virus typically found in Asia and Europe "an unusually mongrelised mix of genetic sequences."[15] This new strain appears to be a result of reassortment of human influenza and swine influenza viruses, in all four different strains of subtype H1N1. Preliminary genetic characterization found that the hemagglutinin (HA) gene was similar to that of swine flu viruses present in U.S. pigs since 1999, but the neuraminidase (NA) and

matrix protein (M) genes resembled versions present in European swine flu isolates. The six genes from American swine flu are themselves mixtures of swine flu, bird flu, and human flu viruses.[16] While viruses with this genetic makeup had not previously been found to be circulating in humans or pigs, there is no formal national surveillance system to determine what viruses are circulating in pigs in the U.S.[17] In April 2009, an outbreak of Influenza-like illness occurred in Mexico and the USA; the CDC reported seven cases of novel A/H1N1 influenza. By April 24 it became clear that the outbreak of ILI in Mexico and the confirmed cases of novel influenza A in the southwest US were related and WHO issued a health advisory on the outbreak of "influenza like illness in the United States and Mexico". [18] The disease then spread very rapidly, with the number of confirmed cases rising to 2,099 by May 7, despite aggressive measures taken by the Mexican government to curb the spread of the disease.[19] On June 11, 2009, the WHO declared an H1N1 pandemic, moving the alert level to phase 6, marking the first global pandemic since the 1968 Hong Kong flu.[20] On October 25, 2009 U.S. President Barack Obama officially declared H1N1 a national emergency[21] Despite President Obama's concern, a Fairleigh Dickinson UniversityPublicMind poll found in October 2009 that an overwhelming majority of New Jerseyans (74%) were not very worried or not at all worried about contracting the H1N1 flu virus.[22] A study conducted in coordination with the University of Michigan Health Service is scheduled for publication in the December 2009 American Journal of Roentgenology warning that H1N1 flu can cause pulmonary embolism, surmised as a leading cause of death in this current pandemic. The study authors suggest physician evaluation via contrast enhanced CT scans for the presence of pulmonary emboli when caring for patients diagnosed with respiratory complications from a "severe" case of the H1N1 flu.[23] March 21, 2010 worldwide update by the U.N.'s World Health Organization (WHO) states that "213 countries and overseas territories/communities have reported laboratory confirmed cases of pandemic influenza H1N1 2009, including at least 16,931 deaths." [24] As of May 30, 2010 worldwide update by World Health Organization(WHO) more than 214 countries and overseas territories or communities have reported laboratory confirmed cases of pandemic influenza H1N1 2009, including over 18,138 deaths. [25] The research team of Andrew Miller MD showed pregnant patients are at increased risk.[26] It has been suggested that pregnant women and certain populations such as native North Americans have a greater liklihood of developing a T helper type 2 response to H1N1 influenza which may be responsible for the systemic inflammatory response syndrome that causes pulmonary edema and death. [27]