Impact of MHC class I diversity on immune control of Immuno-deficiency virus replication
Speaker
P.RAMESH
PH.D SCHOLAR
ANIMAL
BIOCHEMISTRY
INTRODUCTION
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
Major classes of MHC molecules:
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
Cont….
Schematic diagram of class I MHC molecule
Cont….
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
Role of CD8+cells in control of HIV replication
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)
Cont….
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
Cont….
Diverse distribution of HLA-B alleles worldwide
Cont….
Diversity of aminoacids at position 2 in Peptides
Cont….
HIV life cycle
HIV infection is basically 4 stages:
I. Incubation Period
II. Acute Infection
III.Latency Stage
IV.AIDS
HIV Lifecycle
T Cell
CD4
Proteins which are synthesized by HIV
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
HIV infected individuals expressing HLA-B*27
for epitope of KRWIILGLNK (KK10, Gag)
Gag epitope TSTLQEQIAW (TW10) is target
for HLA-B*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
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
Schematic model of Immune control of HIV by HLA alleles presenting Gag epitopes
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 regulatesWhy are Gag specific T-cell Responses Important???
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??
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
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
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
HIV Treatment: Anti Viral Drugs
X
X
Reverse Transcription Inhibitors
Protease Blockers
Antibodies
Bind virus; neutralize or stop virus
from infecting cells; eliminate virus
Cytotoxic T lymphocytes (CTL)
Recognize cells infected with virus
and kill those cellsWhat might a successful Vaccine Do
HIV Vaccine Approaches
Protein subunit
Synthetic peptide
Inactivated Virus
Live-attenuated Virus
Live-vectored Vaccine
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
THANKS
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