1. Impact of MHC class I diversity
on immune control of Immunodeficiency virus replication
Speaker
P.RAMESH
PH.D SCHOLAR
ANIMAL BIOCHEMISTRY

2. Major Histocompatibility Complex (MHC) present in
Antigen Presenting Cells (APC) & all nucleated cells
GLYCOPROTEIN in nature
MHC play important role to discriminate self & non-self
Participates in development of both humoral & cell
mediated immune response
T cells recognize Ag only it combined with an MHC
molecule
INTRODUCTION

3. Major classes of MHC molecules:
Cont….
Class I MHC (all nucleated cells)
Class II MHC (APC)
Class III MHC (inflammation & complement activation)
MHC is referred as HLA complex in humans & H-2
complex in mice

4. Cont….
Schematic diagram of class I MHC molecule

5. In 2007, there was estimated 2.5 million HIV-deaths
Antiretroviral therapy came in mid 1990s
Demand for an effective HIV vaccine (T cell based
vaccines) came in 2007, but aburptly halted because of
lack of efficiency
Central role of MHC class I control of immunodeficiency
virus replication
Introduction to Immunodeficiency Virus

6. Cont….
During Acute infection,
increase in viremia 107
HIV RNA copies/ml
After a few weeks, a
viral set point is 30,000
HIV RNAs
Temporal association
HIV-CD8+ cytotoxic T
cells (CTL)
Role of CD8+cells in control of HIV replication

7. Cont….

8. Cont….
Class I MHC molecules encoded by A, B & C loci in
humans (HLA-A, HLA-B & HLA-C)
3 additional lines supports central role of CD8+
Tcells
First, HLA class I molecules are constantly associated with
particular HIV disease outcomes
Second, more rapid disease progression observed in
individuals with HLA class I homozygosity
Third, selection of particular viral mutant that escape CD8+
Tcell recognition & loss of immune control

9. Cont….
Diverse distribution of HLA-B alleles worldwide

10. Cont….
Diversity of aminoacids at position 2 in Peptides

11. HIV infection is basically 4 stages:
I. Incubation Period
II. Acute Infection
III. Latency Stage
IV. AIDS
HIV life cycle

12. CD4
T Cell
HIV Lifecycle

13. Proteins which are synthesized by HIV

14. Gag, regulatory proteins (Vif,Vpr,Vpu,Nef,Tat & Rev),
Pol proteins (protease), RT & Integrase
All are synthesized early in the viral life cycle
Recent data indicates incoming virus carries Gag &
Pol
Nef down regulates expression of MHC class I
molecules (HLA-A, HLA-B & but not HLA-C)
Control of HIV by HLA-B Gag specific responses

15. HIV infected individuals expressing HLA-B*27 for
epitope of KRWIILGLNK (KK10, Gag)
Gag epitope TSTLQEQIAW (TW10) is target for HLAB*57
Mutations within the epitope, had a high level of
viraemia
Striking feature of viral escape mutations in KK10 &
TW10 epitopes occurs late in the course of infection
HLA-B*27/57 alleles control of HIV replication

16. To address the Question of whether the protein
specificity of HIV specific CD8+ Tcell response is
related to successful immune control ????
Association b/w HIV with Gag specific response is
very important than Nef & Env specific CD8+ Tcell
Control of HIV by HLA-B Gag specific responses

17. Schematic model of Immune control of HIV by HLA alleles presenting
Gag epitopes

18. Gag is highly immunogenic, but also very
conserved in sequence
Gag specific CD8+ T cells may be able to recognize
and kill virus infected cells sooner after infection
than non-Gag specific CD8+ T cells
Pol specific CD8+ T cells also recognize SIV
infected cells within 2 hrs of infection & eliminate
virus infected cells by 6 hrs post infection before
MHC I down regulates
Why are Gag specific T-cell Responses Important???

19. Explanation for central role of HLA-B, compared with
HLA-A & HLA-C in the control of virus replication is
even less clear
Natural killer (NK) cells express killer
immunoglobulin like receptors (KIRs) that recognize
MHC class I molecules
HLA class I alleles are strongly associated with
control of a HIV are those that contain Bw4motif (a
ligand for KIRs)
Why HLA-B restricted T-cell Responses Important??

20. HLA-B restricted CD8+ T cell responses are
more polyfunctional
On the basis of cytokine production
Proliferative capacity
Why this might be the case remains unclear

21. Polyfunctionality of CD8+ T cells are produces
Intereron-
Cytokines (Interleukin-2, Chemokines)
Granzymes
Perforin
Dysfunctionality might be reflected by expression
of PD1 (Programmed cell Death1) a marker of T-cell
exhaustion
Polyfunctionality of effective CD8+ T cells

22. Similar to CTLA-4 (cytotoxic T-lymphocyte antigen4),
PDI is a member of B7-CD28 family of
immunoregulatory molecule
PDI & CTLA-4 is expressed at a particularly high
levels by HIV specific CD8+ & CD4+
Expression of PDI prevent over activation of the
immune response & consequent Autoimmunity
Blockade of PDI & CTLA-4 pathway demonstrates
potential immunotherapy for HIV infected subjects
Polyfunctionality of effective CD8+ T cells

23. HIV Treatment: Anti Viral Drugs

24. Reverse
Transcription
Inhibitors
Protease Blockers
X

25. Antibodies
Bind virus; neutralize or stop virus from
infecting cells; eliminate virus
Cytotoxic T lymphocytes (CTL)
Recognize cells infected with virus and kill
those cells

26. Protein subunit
Synthetic peptide
Inactivated Virus
Live-attenuated
Virus
Live-vectored Vaccine
HIV Vaccine Approaches

28. Thirty-six
years
ago,
President
Kennedy…gave a goal of reaching the
moon, and we achieved it - ahead of
time
Let us today set a new national goal
for science in the age of biology.
Today, let us commit ourselves to
developing an AIDS vaccine within the
next decade
- Former President Bill Clinton
Vaccine development remains the #1 priority of
AIDS research.
It is the best hope for
protection against HIV infection.