HIV AND IMMUNITY

PRESENTER: DR. FRANK GITONGA

MODERATOR: DR. T. MWENDWA
 Learning Objectives

 To understand the process of viral infection and

replication
 To appreciate the innate and adaptive responses to
HIV infection
 To appreciate some surgical and anaesthetic
implications of HIV infection and
immunopathogenesis
 OUTLINE
 Structure of HIV
 Viral Replication
 Immunobiology of HIV-an Overview
 Innate Immune Response to HIV infection
 Adaptive Immune response to HIV infection
 Immunopathogenesis
 Mechanisms of immune system evasion
 HIV Infection- some clinical implications
 CHARACTERISTICS

 Icosahedral (20 sided), enveloped virus of the

lentivirus subfamily of retroviruses.
 Retroviruses transcribe RNA to DNA.
 Two viral strands of RNA found in core surrounded by
protein outer coat.
 Outer envelope contains a lipid matrix within which
specific viral glycoproteins are imbedded.
 These knob-like structures responsible for binding to
target cell.
 HIV Proteins

 Envelope (env) glycoproteins - gp160

precursor- gp120, gp41
 Group antigen (gag) proteins - p24 (core), p17
(scaffold)
 Polymerase (pol) proteins - p66 and p51
(reverse transcriptase), HIV protease, p32
(endonuclease)
 Regulatory proteins - tat, rev, vif, nef
[nef deleted virus vaccine]
 Viral Replication
 Binding and Internalization
 Reverse transcription & DNA
incorporation
 Transcription & translation of viral
genes
 Assembly and budding
 Cell activation and its role in viral
replication
 CLASSES OF DRUGS USED
IN ART

 Nucleoside/nucleotide reverse transcriptase inhibitors

(NRTIs/NtRTIs)
 Non-nucleotide reverse transcriptase inhibitors
 Protease inhibitors
 Fusion inhibitors
 CCR5 co-receptor antagonists
 Integrase inhibitors
 Life cycle
Acute Viral phase
Declining Viremia
Steady state
Latency
AIDS
 Immune Responses in
HIV
 HIV is lymphotropic: CD4+ lymphocytes.
 The loss of CD4+ cells- viral pathogenesis,
immunopathogenesis, apoptosis, Bystander
phenomenon
 Cytotoxic response
 Opportunistic infections
 Th-1 to Th-2 cytokine shift
 There are 3 major forms of HIV in the body: Cell
Associated Virus, Free Virus and FDC associated
virus
 Innate Immune Responses to HIV
Infection- Humoral components

1. Complement system- the Classical, Alternative

and the Lectin pathways
 Activation of the complement system via gp120 and
gp41, even in the absence of HIV-specific
antibodies, and is hence already coated with
complement fragments at the initial stages of
infection.
 Opsonization
 Innate Immune Response

 Activates adaptive immunity- Antigen

presentation, Dendritic cells, C3, activation
of T cell Immunity.
 Creation of viral reservoir- interactions
between complement and complement
receptors at Follicular Dendritic cells (FDC)
in Germinal centers creates reservoirs of
HIV.
 Innate Immune Responses to HIV
Infection- Humoral components

2. Role of Cytokines , Interferons and

Chemokines in acute HIV infection- IFNα,
TNF α, IL-6 IL-10, IL-15
 HIV-1 activates plasmacytoid dendritic cells
(pDCs) via toll like receptors (TLRs) and
induces the secretion of IFNα in acute HIV-
infection
 Innate Immune Responses to HIV
Infection- Humoral components

 IFN-secretion during infection causes

symptoms like fever or aching muscles. IFNα
inhibits HIV replication, inhibits HIV gene
expression, viral assembly and budding
 Activation of immune cells, such as NK cells
or macrophages, and upregulating antigen-
presentation to T cells.
 Innate Immune Responses to HIV
infection- Cellular Components
1. Dendritic cells
a. Langerhans cells
 First Line of defense against Mucosal infection: first cells
to encounter HIV (location: mucosal stfd. epithelium)
 Mature LC present antigens to T cells hence initiating
adaptive immune responses
 Attachment of HIV-gp120 to Langerin leads to
internalization of the viral particle and subsequent
degradation in the Birbeck granules, that are
characteristic for LCs
 Prevent transmission to main target cell- CD4 T cell.
 Explains role of VMMC in reducing HIV infection.
 Innate Immune Responses to HIV Infection-
Cellular Components

b. Interstitial Dendritic cells

 Location: dermis, vaginal, oral and colonic
lamina propria
Dendritic cell-specific ICAM-3-grabbing non-integrin
(DC-SIGN) on dermal DCs is implicated in the
transfer of HIV to T cells in the lymph nodes
Dermal DCs contribute not only to shuttle HIV from
the mucosal site to the lymphatic tissue but also to
efficiently transmit of HIV to its main targets, CD4+
T cells.
 Innate Immune Responses to HIV
Infection- Cellular Components

c. Plasmacytoid Dendritic cells

 Type 1 Interferon producing cells
 HIV reduces the number and
function of this and other cellular
components causing alterations
in cytokine microenvironment
 Innate Immune Responses to
HIV Infection- Cellular Components

d. NK and NKT cells

 Plasmacytoid dendritic cells interact with
NK cells bidirectionally. DC editing
 “Natural” killer cells
 NK Cells release cytokines and chemokines
 IL 12 and Interferon gamma are potent
activators of NK cells
 Innate Immune Response

 NK cells have receptors that detect the

presence of class I MHC proteins on the
cell surface. If a cell displays sufficient class
I MHC proteins, that cell is not killed by the
NK cell.
 Virus-infected cells and tumor cells display
a significantly reduced amount of class I
MHC proteins, and it is those cells that are
recognized and killed by the NK cells.
 Innate Immune Responses
to HIV Infection
 NK cells have direct cytotoxic activity against virus
infected cells. NK cells secrete cytotoxins -Perforins
and Granzyme.
 Fas-Fas Ligand mediated apoptosis
 Antibody dependent cellular cytotoxicity (ADCC)-
IgG
 Chronic viral stimulation causes NK cell exhaustion
or Anergy
 NK cells- tumor immunology- MICA protein
 NK T cells- Tumor development in HIV
 Innate Immune Responses to HIV
Infection- Cellular Components

e. Macrophages
 Major cellular HIV Reservoir
 Infectious virus is retained in macrophages
 Are resistant to cytopathic effects of HIV
 Contribute to persistence and spread of the
virus
 Once ingested by macrophages the virus
escapes immune surveillance.
 Virological synapse forms between macrophage
and T cell and the virus is efficiently
transmitted.
 Innate Immune Responses to HIV
Infection- Cellular Components

f. Monocytes
 Neuropathogenesis of HIV
infection. HIV Dementia
 Induction of pro-inflammatory
cytokines and neurotoxins that
disrupt BBB and B-CSF-Barriers
facilitating entry of infected
monocytes into CNS
 Adaptive Immune
Response to HIV
 The responses come in two forms:
cellular and humoral. The cellular
response refers to the activity of the
CD4 and CD8 T cells, the latter known as
cytotoxic lymphocytes. The humoral
response refers to antibody production
and activity.
 Adaptive Immune
Response to HIV
 CD8 T cells act against HIV in two different
ways during primary infection:
1. by directly killing HIV-infected cells
2. by secreting anti-HIV molecules such as
chemokines
 CD4/CD8 cell ratio: The normal ratio is about 1
to 1.5. If the disease is progressing, CD4 will
decline and CD8 will stay the same or increase
and the CD4/CD8 ratio will be <1, indicating
disease progression
 Adaptive Immunity

HIV Specific Neutralizing

antibodies
CTL responses
T Helper cell responses
 Adaptive Immune
Response to HIV
 Neutralizing antibodies
Non-neutralizing antibodies appear 2-4
wks after infection. Form the basis for dx
of HIV infection by ELISA
Neutralizing antibodies appear 8wks after
infection
Under T cell control, produced by B cells
Seroconversion
 Adaptive Immune
Response to HIV
 Cytotoxic T lymphocytes
 They recognize HIV infected cells through HIV
antigens expressed on the surface of the infected
cells in association with HLA Class I peptides.
 Cytotoxic T cells have no effect on free virus, only
on virus infected cells
 CD8 T cells also produce chemokines e.g CD8
Antiviral factor (CAF) that inhibit viral replication.
 Cytotoxic response- Granzymes and Perforins,
Caspases activate Apoptosis, ADCC, Fas-FasL
mediated apoptosis
 Immunopathogenesis
• Direct and Indirect Effects of HIV on CD4+ T Cells
• Direct or viral pathogenesis is shown as the death of
CD4+ T cells by viral cytopathicity, which is the
consequence of HIV infection of CD4+ T cells.

• Indirect or immunopathogenesis involves infection of

APC that leads to modification of expression of a
number of APC molecules. This effect includes
downregulation of IL-12, and upregulation of Fas, as well
as expression of FasL.

• Apoptosis
 Mechanisms by which HIV
evades the Immune system
• Viral latency
• Inhibition of antigen presentation
• Mutation of viral epitopes compromising
recognition by CTLs or Immunoglobulins- “Viral
escape”
• T cell anergy
• Retention of infectious virus particles sufficient
to maintain a low level of infection, despite the
dramatic decline in plasma viremia
• Escapes Complement Mediated Lysis via RCAs.
 HIV Infection- Clinical
Implications

•Surgery enhances immunosuppression in HIV.

Major surgery leads to suppression of Th 1 cells
and the cytokines produced by them IL-2 and
IFN gamma.
•Immune reconstitution: IRIS
•Malignancies including; Kaposi's sarcoma, Non-
Hodgkin’s lymphoma, Ca Cervix, Squamous cell
carcinoma
 HIV Infection- Clinical
Implications
•Surgical- site infections
•Opportunistic Infections
•Thrombocytopenia
•Intracranial mass lesions e.g.
lymphoma, tuberculoma,
toxoplasmosis. ( ICP), Autonomic
neuropathy
 HIV Infection- Clinical
Implications

Cardiac manifestations-
premature atherosclerosis, MI,
Myocarditis, Multifocal
Abdominal aortic aneurysms
Wound healing and Graft take
 Pre-operative considerations

•The preoperative evaluation of HIV-infected

patients should be the same as that for non-HIV-
infected patients
•Immunocompetence- CD4 Count
•Organ dysfunction
•Drug interactions
•Anaemia and Thrombocytopenia
 REFERENCES

1. Lange Microbiology and Immunology Review 10th

Edition Chapter 58- Cellular Basis of The Immune
Response
2. Harrison’s Principles of Internal Medicine 17th
Edition- Chapter 182
3. Stoelting Anaesthesia and Co-existing Disease 6th
Edition