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AIDS is caused by human immunodeficiency virus Genetically the virus has two types HIV-1 (World wide) HIV-2 which is less aggressive slow and restricted mainly to western Africa.
CONCENTRATION OF VIRUS
Blood, Menstrual Blood Very High Vaginal Fluids, Semen, Pre ejaculate Fluid High Bone Marrow High Saliva No Sweat, Tears, urine - No
26
Blood 18,000
Semen 11,000
Saliva 1
HIV STRUCTURE
HIV belongs to a special class of viruses called retroviruses. Within this class, HIV is placed in the subgroup of lentiviruses. Other lentiviruses include SIV, FIV, Visna and CAEV, which cause diseases in monkeys, cats, sheep and goats. All viruses except retroviruses contain DNA
HIV STRUCTURE
So Retroviruses are the exception because their genes are composed of RNA (Ribonucleic Acid). However RNA has a very similar structure to DNA with small differences
HIV STRUCTURE
HIV has just nine genes (compared to more than 500 genes in a bacterium Three of the HIV genes, called gag, pol and env, contain information needed to make structural proteins for new virus particles.
HIV STRUCTURE
The other six genes, known as tat, rev, nef, vif, vpr and vpu, code for proteins that control the ability of HIV to infect a cell, produce new copies of virus, or cause disease.
HIV STRUCTURE
An HIV particle is around 100-150 billionths of a metre in diameter. That's about the same as: 0.1 microns 4 millionths of an inch one twentieth of the length of an E. coli bacterium one seventieth of the diameter of a human CD4+ white blood cell.
HIV STRUCTURE
HIV particles surround themselves with a coat of fatty material known as the viral envelope . This envelope gives out lots of little spikes around 72 in number.
HIV STRUCTURE
These spikes are made of knobs and handles made of proteins gp120 and gp41 respectively.
HIV STRUCTURE
Just below the viral envelope is a layer called the matrix, which is made from the protein p17(Matrix proteins)
HIV STRUCTURE
Below the matrix is another layer of proteins P24 forming viral core (or capsid) and is usually bulletshaped.
HIV STRUCTURE
Inside the core are three enzymes required for HIV replication called Reverse transcriptase Integrase And protease
HIV STRUCTURE
Also held within the core is HIV's genetic material, which consists of two identical copies of single stranded RNA.
The virus, entering through which ever route, acts primarily on the following cells:
* Lymphoreticular system: o CD4+ T-Helper cells o CD4+ Macrophages o CD4+ Monocytes o B-lymphocytes *
The virus, entering through which ever route, acts primarily on the following cells:
Certain endothelial cells * Central nervous system: o Microglia of the nervous system o Astrocytes o Oligodendrocytes o Neurones - indirectly by the action of cytokines and the gp-120
Pathogenesis
HIV binds to CD4 molecule, CD4 molecule is found on the T helper-cell Macrophages etc.Binding of CD4 is not sufficient for entry Therefore gp120 protein also binds to coreceptor CCR5 Co-receptor - is used by macrophages CXCR4 Co-receptor - is used by lymphocytes
Pathogenesis
Binding of virus to cell surface results in fusion of viral envelope with cell membrane of T-helper cell and thus Viral core is released into cell cytoplasm After uniting with T-helper cells the T-Helper cells through Th1 - activate Tc (CD8) lymphocytes, promoting cellmediated immunity Th2 - activate B lymphocytes, promoting antibody mediated immunity
Pathogenesis
CD8 Cytotoxic T lymphocyte (CTL) is Critical for containment of HIV.Derived from T8 cells, recognize viral antigens and directly destroy infected cells
Pathogenesis
Antibodies formed bind to surface of virus to prevent attachment to target cells Fc portion of antibody also binds to NK cells and Stimulates NK cell to destroy infected cell
Pathogenesis
Numerous organ systems are infected by HIV: Brain: macrophages and glial cells Lymph nodes and thymus: lymphocytes and dendritic cells Blood, semen, vaginal fluids: macrophages Bone marrow: lymphocytes Skin: langerhans cells Colon, duodenum, rectum: chromaffin cells Lung: alveolar macrophages
Pathogenesis
About (10 billion) virions are produced daily Average life-span of an HIV virion in plasma is ~6 hours Average life-span of an HIV-infected CD4 lymphocytes is ~1.6 days HIV hides in cells like CNS etc and can lie dormant within a cell for many years, especially in resting (memory) CD4 cells, unlike other retroviruses etc
Pathogenesis
All elements of immune system are affected. Advanced stages of HIV are associated with destruction and disruption of lymphoid tissue(Thelper cells etc) that result in
Impaired ability to mount immune response Impaired ability to maintain memory responses Loss of containment of HIV replication ultimately results in severe immunosuppression susceptibility to opportunistic infections
Window period
The window period begins at the time of infection and can last 4 to 8 weeks. During this period, a person is infected, infectious and viremic, with a high viral load and a negative HIV antibody test. The point when the HIV antibody test becomes positive is called the point of seroconversion.
Window Period
Some times 90 percent of cases test positive within three months of exposure 10 percent of cases test positive within three to six months of exposure
Stage 1 - Primary
Short, flu-like illness - occurs one to six weeks after infection Or there may be no symptoms at all
Stage 2 - Asymptomatic
Lasts for an average of ten years
Stage 3 - Symptomatic
The symptoms are now moderate more often and prolonged The immune system deteriorates
AIDS-DEFINING DISEASES
Oesophageal candidiasis Cryptococcal meningitis Chronic cryptosporidial diarrhoea CMV retinitis or colitis Chronic mucocutaneous herpes simplex Disseminated Mycobacterium avium intracellulare Pulmonary or extrapulmonary tuberculosis Pneumocystis carinii (jirovecii) pneumonia
AIDS-DEFINING DISEASES
Progressive multifocal leucoencephalopathy Recurrent non-typhi Salmonella septicaemia Cerebral toxoplasmosis Extrapulmonary coccidioidomycosis Invasive cervical cancer Extrapulmonary histoplasmosis Kaposi's sarcoma Non-Hodgkin lymphoma Primary cerebral lymphoma HIV-associated wasting HIV-associated dementia
Being that HIV reduces immunologic activity, the intraoral environment is a prime target for chronic secondary infections and inflammatory processes, including OHL, which is due to the Epstein-Barr virus under immunosuppressed conditions
Pneumocystis pneumonia
X-ray of Pneumocystis jirovecii caused pneumonia. There is increased white (opacity) in the lower lungs on both sides, characteristic of Pneumocystis pneumonia
Pneumocystis pneumonia
Pneumocystis pneumonia (originally known as Pneumocystis carinii pneumonia, and still abbreviated as PCP, which now stands for Pneumocystis pneumonia) is relatively rare in healthy, immunocompetent people, but common among HIVinfected individuals. It is caused by Pneumocystis jirovecii.
Immunologic Manifestations
Antibodies are produced to all major antigens.
First antibodies detected produced against gag proteins p24 and p55. Followed by antibody to p51, p120 and gp41 As disease progresses antibody levels decrease.
ELISA Testing
First serological test developed to detect HIV infection.
Easy to perform. Easily adapted to batch testing. Highly sensitive and specific.
Antibodies detected in ELISA include those directed against: p24, gp120, gp160 and gp41, detected first in infection and appear in most individuals
Western Blot
Most popular confirmatory test.
Utilizes a lysate prepared from HIV virus. The lysate is electrophoresed to separate out the HIV proteins (antigens). The paper is cut into strips and reacted with test sera. After incubation and washing anti-antibody tagged with radioisotope or enzyme is added. Specific bands form where antibody has reacted with different antigens. Most critical reagent of test is purest quality HIV antigen. The following antigens must be present: p17, p24, p31, gp41, p51, p55, p66, gp120 and gp160.
Western Blot
Antibodies to p24 and p55 appear earliest but decrease or become undetectable. Antibodies to gp31, gp41, gp 120, and gp160 appear later but are present throughout all stages of the disease.
Western Blot
Interpretation of results.
No bands, negative. In order to be interpreted as positive a minimum of 3 bands directed against the following antigens must be present: p24, p31, gp41 or gp120/160.
Western Blot
Expensive $ 80 - 100 technically more difficult visual interpretation lack standardisation
- performance - interpretation - indeterminate reactions resolution of ??
Virus isolation
Virus isolation can be used to definitively diagnose HIV. Best sample is peripheral blood, but can use CSF, saliva, cervical secretions, semen, tears or material from organ biopsy. Cell growth in culture is stimulated, amplifies number of cells releasing virus. Cultures incubated one month, infection confirmed by detecting reverse transcriptase or p24 antigen in supernatant.
Urine Testing
Urine Western Blot
As sensitive as testing blood Safe way to screen for HIV Can cause false positives in certain people at high risk for HIV
Oral Testing
Orasure
The only FDA approved HIV antibody. As accurate as blood testing Draws blood-derived fluids from the gum tissue. NOT A SALIVA TEST!
Indirect immunofluorescence
Can be used to detect both virus and antibody to it. Antibody detected by testing patient serum against antigen applied to a slide, incubated, washed and a fluorescent antibody added. Virus is detected by fixing patient cells to slide, incubating with antibody.
Virus isolation
Virus isolation can be used to definitively diagnose HIV. Best sample is peripheral blood, but can use CSF, saliva, cervical secretions, semen, tears or material from organ biopsy. Cell growth in culture is stimulated, amplifies number of cells releasing virus. Cultures incubated one month, infection confirmed by detecting reverse transcriptase or p24 antigen in supernatant.
Testing of Neonates
Difficult due to presence of maternal IgG antibodies. Use tests to detect IgM or IgA antibodies, IgM lacks sensitivity, IgA more promising. Measurement of p24 antigen. PCR testing may be helpful but still not detecting antigen soon enough: 38 days to 6 months to be positive.
Combination Therapy
Combination therapy often called HAART is standard care for people with HIV. Monotherapy created virus resistance to the individual drug. Some combination therapies increase the time it takes for the virus to become resistant. Combinations of a PI or NNRTI with one or two NRTIs is often recommended. Combination therapy may reduce individual drug toxicity by lowering the dosage of each drug
Treatment
HAART: Highly Affective Anti-Retro Viral Therapy: Anti-retro viral therapy is recommended if: Patient is asymptomatic/ symptomatic + CD4 count of <350/l / any AIDS defining condition / plasma HIV RNA greater than 100,000 copies/ml
Treatment
Integrase inhibitors: Raltegravir Maturation Inhibitors under trails: Bevirimat & vivicon
Treatment
For needle stick: Post exposure Prophylaxis ZDV+3TC 28 days, but in high risk (high viral RNA copies) a combination of ZDV+3TC+Indinavir Pregnancy: ZDV full dose, trimester 2 and 3+ 6 weeks to neonate reduces vertical transmission by 80% ZDV restricted to intrapartum period + NEVIRAPINE- 1 dose at onset of delivery+ AZT+3TC for 1 week after delivery Neonate: 1 dose of Nevirapine within 24-72 hrs after birth + ZDV for 1 week
Symptomatic tx and antibiotics/antivirals/glucocorticoids/thalidomide /antifungals/metronidazole for bacterial, viral, autoimmune, fungal and parasitic infections.
Nucleotide
Tenofovir
1 PI 1 NNRTI
3rd NRTI is abacavir 1 nucleotide RTI (Tenofovir) 2 PI (ritonavir as booster)
Choice of Regimen
NNRTIs
Nevirapine (2 tab) Efavirenz (3 cap) Delavridine (6 or 12)
PIs
Indinavir (6 or 12 cap) Nelfinavir (10 tab) Ritonavir (dont even go there) Saquinavir soft gel (18 cap) Amprenavir (16 cap) Lopinavir/ritonavir (6 cap)
Drug holidays or treatment interruptions result in rapid viral rebound within 2 to 3 weeks of treatment discontinuation Simplification of dosing regimens to twice or once daily may improve long-term adherence
Summary
When to start treatment
CD4<350 VL> 55,000
Appropriate prophylaxis
Primary: PCP, MAC Secondary: PCP, MAC, Toxo, candidiasis, CMV, etc.
Nucleotide Analogues
Tenofovir Dose: 300 mg once daily Take with food for optimal absorption
Delavirdine Efavirenz
Usual Dose 200 mg QD x14 days, then 200 mg BID 400 mg TID 600 mg QD
Usual Dose 400 mg BID with RTV 1200 mg TID 800 mg q8h 600 mg BID 400 mg BID with SQV 750 mg TID or 1250 mg BID 1200 mg BID 400 mg lopinavir/100 mg ritonavir BID= 3 caps BID
TM
Viral co receptor antagonists compete for binding at the CXCR4 (X4) and CCR5 (R5) coreceptors
bicyclams and ligands
Drug holidays or treatment interruptions result in rapid viral rebound within 2 to 3 weeks of treatment discontinuation Simplification of dosing regimens to twice or once daily may improve long-term adherence
Protected Sex
Use condoms (female or male) every time you have sex (vaginal or anal) Always use latex or polyurethane condom (not a natural skin condom) Always use a latex barrier during oral sex
THANK YOU
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