“Oh GOSH! Reflecting on Hackteria's Collaborative Practices in a Global Do-It...
Impact of MHC class I diversity on immune control of Immuno-deficiency virus replication
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
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
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
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
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
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.