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