BCM01: Immunology

HIV/AIDS Immunology

Prof. Takafira Mduluza

Ph.D ; M.Phil.; BAppl.Sc (Biol. & Biochem.)
Room 101/102
Biochemistry Department- University of Zimbabwe

•  Contact: mduluza@medic.uz.ac.zw

• 
tmduluza@yahoo.com

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@Prof. Takafira MDULUZA, PhD

Number of people living with HIV/
AIDS

Total


40.0 Million

Adults


37.1 Million

Women


18.5 Million

Children < 15 years

3.0 Million



UNAIDS, 2002

@Prof. Takafira MDULUZA, PhD

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Adults and children estimated to be living with HIV/AIDS as of end 2001.
@Prof. Takafira MDULUZA, PhD
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People newly infected with HIV in
2002

Total


5.0 Million

Adults


4.2 Million

Women


2.0 Million

Children < 15 years

800,000





@Prof. Takafira MDULUZA, PhD
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 Spread of HIV in Africa, 1984-1999. 
Estimated HIV prevalence rate in 15-49 year olds in
Sub-Saharan countries

@Prof. Takafira MDULUZA, PhD

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Figure 1. Evolution and Mutation of the
Human Immunodeficiency Virus (HIV).

HIV most likely arose from the chimpanzee

simian immunodeficiency virus (SIV). After
many cycles of viral replication in its human
host, it evolved to a consensus virus with
mutations in genes that encode dominant
immunogenic peptides. These mutations hinder
the presentation of such peptides to cytotoxic T
lymphocytes (CTLs) by the most prevalent
HLA molecules in the population. As this
consensus virus continues to multiply, selective
pressures engendered by the immune system of
the new host force the emergence of viruses
with escape mutations that enable infected cells
to avoid being recognized by cytotoxic T
lymphocytes.

@Prof. Takafira MDULUZA, PhD

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 Early and Acute HIV-1C Infection in Botswana /
Neutralizing antibodies & Viral Set Point in Primary HIV-1C Infection
Tshedimoso
design
Primary HIV-1 infection

Acute HIV-1 infection
Early HIV-1 infection

(pre-seroconversion)
(seroconversion)

Viral load at peak

HIV-1 antibodies

Viral load at set point (Viral Set Point)

Viral load

14 days
21 days
35 days
84 days
Time after HIV-1 infection
1 year



Time of infection

@Prof.
Adapted from Acute Infection studyTakafira MDULUZA,
design: PhD
et al, study design at BHP.

Novitsky 7

 Early and Acute HIV-1C Infection in Botswana /
Neutralizing antibodies & Viral Set Point in Primary HIV-1C Infection

Primary HIV-1 infection

Acute HIV-1 infection
(pre-seroconversion)


Early HIV-1 infection
(seroconversion)

High Viral Set Point

Viral load

Low Viral Set Point

Time after HIV-1 infection

1 year
Neutralizing antibodies

@Prof.
Adapted from Acute Infection studyTakafira MDULUZA,
design: PhD
et al, study design at BHP.

Novitsky 8

 AIDS deaths in 2002

Total


3.0 Million

Adults


2.4 Million

Women


2.0 Million

Children < 15 years

580,000



UNAIDS

@Prof. Takafira MDULUZA, PhD

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 INTERVENTIONS

•  Interventions to influence behavior, education

•  Promotion of condom use

•  Diagnosis and treatment of STDs

•  Harm reduction strategies for IV drug users

•  Antiretrovirals : impact or vertical (PMTCT) and horizontal
(?) transmission

•  Political commitment

@Prof. Takafira MDULUZA, PhD

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HIV DISEASE 1996 - 2000

A potentially manageable disease, at

least over a decade time scale

@Prof. Takafira MDULUZA, PhD

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 HIV INFECTION

•  HIV infection is usually transmitted by clinically healthy

carriers of the virus

•  HIV may take ten years or more to manifest itself
clinically

•  A large proportion of HIV-infected people (almost all in
the absence of antiretroviral treatment) eventually develop
AIDS

@Prof. Takafira MDULUZA, PhD

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 Proportion of HIV infection
worldwide by route of acquisition



Percentage

Blood transfusion

3 - 5

Perinatal transmission

10 - 20

Sexual intercourse

70 - 80

Injecting drug use

5 - 10

Health care workers

< 0.01

@Prof. Takafira MDULUZA, PhD

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 MOTHER TO CHILD TRANSMISSION

•  Vertical transmission of HIV can occur

•  BEFORE : intrauterine

•  DURING : intrapartum

•  AFTER BIRTH : breast feeding

@Prof. Takafira MDULUZA, PhD
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 NATURAL HISTORY OF HIV DISEASE

clinical
seroconversion latency progression AIDS

virus

CD4

months Years
@Prof. Takafira MDULUZA, PhD
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 PROGRESSION TIME TO AIDS
SAN FRANCISCO CITY CLINIC COHORT

2 years : 1 %

5 years : 11 %

10 years : 51 %

15 years : 79 %

@Prof. Takafira MDULUZA, PhD

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 CD4 T CELL DEFICIENCY AND PROGRESSION TO AIDS

AIDS
CD4 candidiasis

zoster HIV
kaposi

lymphomas
pneumocystis
toxoplasmosi
200 CMV
MAC

Months Years

Primary infection@Prof. Takafira

Clinical latency
MDULUZA, PhD
phase AIDS17

Why NAbs are considered important to HIV/AIDS Vaccines

• 2G12 and b12 are produced against gp120

conformational epitopes overlapping the CD4
receptor , therefore interfere with virus
attachment to target cells,

• 4E10 and 2F5 are produced against

distinct adjacent epitopes on the
membrane proximal external region
(MPER) of gp41, therefore prevent fusion
of HIV with the target cell

@Prof. Takafira MDULUZA, PhD

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Antibodies in immunity

@Prof. Takafira MDULUZA, PhD

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Classification of HIV

HIV-21

Group M2 Group N Group O

Clades A, B3, C, D, F, F2, G, H, J, K

Recombinants: Common: AE, AG

Uncommon: AGHK, FD, AFGHJK, AB, BC
1 HIV-1 most common, but HIV-2 now circulating outside Africa,
especially India
2 Most infections due to group M viruses
3 Clade B: 98–99% USA, 90% Europe

@Prof. Takafira MDULUZA, PhD

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McCutchenn F, et al. XIII IAC, 2000. Abstract 165
 HIV DIVERSITY

•  Mutation

•  Recombination

–  Geographic intermixing of subtypes

–  Co-infection of individuals

–  Co-infection of susceptible cells

@Prof. Takafira MDULUZA, PhD

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PATHOGENESIS

@Prof. Takafira MDULUZA, PhD

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 Decreases in CD4+ T-Lymphocyte
count associated with HIV infection
CD4+ T-Lymphocyte count (cells/mm )
3

Primary
1,200

HIV RNA copies per ml Plasma

infection ± Acute HIV syndrome Death
1,100 Wide dissemination of virus
1,000 Seeding of Lymphoid Organs
Opportunistic
900 disease
Clinical latency
800
700
600 Constitutional
500 symptoms
400
300
200
100
0
0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11+
Weeks Years
@Prof. Takafira MDULUZA, PhD
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Modified from Fauci et al. Ann Int Med 1995;124:654
 NATURAL HISTORY OF HIV DISEASE

CD4 CD4
CD8 Virus

Virus CD8

Fast progressors
CD4

CD8
Virus

@Prof. Takafira MDULUZA, PhD

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Slow progressors
 Immune Response in Primary Infection

Chemokines
IFNγ

CTL

Neutralizing Abs

CD4 help

viremia

D0 D7 D20 D40 D60 D80

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 ACUTE HIV INFECTION

Stimulation of HIV specific CD4+ T helper cells

Infection of activated Preservation of activated

helper cells helper cells

Generation of HIV specific CTLs

Loss of HIV-specific
Loss of CTL Maintenance Maintenance of HIV
helper cells
function of CTL function -specific helper cells

PROGRESSION NON PROGRESSION 26

@Prof. Takafira MDULUZA, PhD

 ACUTE INFECTION

•  Clearance of virus is only partial

•  Insufficient anti-viral immune response

•  Integrated proviral DNA and reservoirs

•  Escape mutants

•  ? Protected sites

@Prof. Takafira MDULUZA, PhD

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 RESERVOIR OF LATENTLY
INFECTED CELLS

•  A pool of latently-infected resting CD4+ T

cells is established in primary infection

•  Early antiretroviral therapy fails to prevent

the establishment of the latently-infected
pool of cells

@Prof. Takafira MDULUZA, PhD

28

CERTAIN CYTOKINES BLOCK ENDOGENOUS
HIV-INDUCING CYTOKINES

TGF β, IL-4 block HIV replication in IL-2

stimulated PBMC

IL-10 dose dependently inhibits TNFα - and

IL-6 -induced HIV

@Prof. Takafira MDULUZA, PhD

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 HIV pathogenesis

• Infects CD4+ lymphocytes and

monocytes/macrophages

• Production of 10 billion viruses a day

• In combination with high mutation rate

this leads to large potential for viral
diversity and escape from the immune
response (and drugs)

@Prof. Takafira MDULUZA, PhD

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 SOURCES OF HIV-1

•  SOURCES CONTRIBUTING TO RAPID-PHASE DECAY:



Free virions



T 1/2: < 6 h


Productively infected CD4 cells:

1 d


resting CD4 cells with unintegrated DNA:
16 d





•  LONG-LIVED CELLS COINTRIBUTING TO SLOWER PHASE DECAY:

Virions on follicular dendritic cells:

15 d

Infected macrophages:


>15 d

Resting CD4 cells with integrated DNA:
years

@Prof. Takafira MDULUZA, PhD

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 Eradication
versus
Long term control of HIV

@Prof. Takafira MDULUZA, PhD

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 Continuous virus replication in
lymphoid tissues in CD4 + cells

Lymph-nodes spleen
Gut and genital tract associated
lymphoid tissue
GALT

The@Prof.
circulation / blood
Takafira MDULUZA, PhD
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IMMUNODEFICIENCY INDUCED
BY HIV

•  Chronic activation of the immune system

•  Progressive loss of CD4T cell function

•  Progressive loss of naive CD4T cell
repertoire

@Prof. Takafira MDULUZA, PhD

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@Prof. Takafira MDULUZA, PhD
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Accelerated T-cell destruction leads to
impaired production

@Prof. Takafira MDULUZA, PhD

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FUNCTIONAL DEFECTS OF CD4 T
CELLS IN HIV DISEASE

Activation

Predominant memory phenotype



Decreased Th1 cytokine production



Loss of proliferative responses

@Prof. Takafira MDULUZA, PhD

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 TISSUE MACROPHAGES 
AND DENDRITIC CELLS

Virus reservoir

Induction of immune dysfunction

@Prof. Takafira MDULUZA, PhD

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 HIV-SPECIFIC IMMUNE RESPONSES

•  Antibodies

•  CD4 T cells

•  Cytotoxic T cells

•  CD8- mediated antiviral activity

•  Protective role in the initial response to HIV infection ;
decreased protective role or pathogenic role during the
chronic phase of the disease

@Prof. Takafira MDULUZA, PhD

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 AIMS OT THERAPY

•  Maintain immune function

•  Prevent progression

•  Prolong survival

•  Improve quality of life

@Prof. Takafira MDULUZA, PhD

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 APPROVED ANTIRETROVIRAL DRUGS

•  NUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS

–  Abacavir (ABC)

Stavudine (d4T)
Tenofovir

–  Didanosine (ddI)

Zalcitabine (ddc)

–  Lamivudine (3TC)

Zidovudine (AZT)

•  NON-NUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS

–  Efavirenz


Nevirapine

–  Delavirdine

•  PROTEASE INHIBITORS

–  Amprenavir

Nelfinavir
FosAmprenavir

–  Indinavir


Ritonavir
Atazanavir

–  Lopinavir


Saquinavir
(Tipranavir)



FUSION INHIBITORS

T-20

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 HAART

• Major clinical benefit

• No eradication

• Toxicities

• Cost

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PROBLEMS ASSOCIATED WITH HAART

•  Complexity

•  Short and long terme toxicities

•  Cross-resistance

•  Drug-drug interactions

@Prof. Takafira MDULUZA, PhD

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 NEW SIDE EFFECTS ASSOCIATED
WITH HAART

•  Lipodystrophy

•  Diabetes

•  Hypertriglyceridemia hypercholesterolemia

@Prof. Takafira MDULUZA, PhD

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 First line regimens

2 nucleosides
(zidovudine/lamivudine >= stavudine/lamivudine >
zidovudine/didanosine > didanosine/lamivudine >
stavudine/didanosine)
PLUS
Efavirenz CNS symptoms
Teratogenicity
OR Skin rash
Nevirapine Hepatotoxicity
Abacavir yHypersensitivity
Protease inhibitor Metabolic
(nelfinavir or ritonavir-enhanced abnormalities (GI
indinavir, lopinavir, or saquinavir) intolerance, kidney
stones)
@Prof. Takafira MDULUZA, PhD
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 HAART restores CD4 counts and
reduces the risk of AIDS

CD4 virus

AIDS HAART

500

200

0 0.5 8 0 0.5 years

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 IMMUNE RESTORATION WITH
HAART

•  Increased number of CD4+ lymphocytes

•  Increased number of naive T cells

•  Immune response to recall antigens

•  Increased proportion of cells specific for certain pathogens

•  Increased proportion of IL-2 producing CD4 T cells to anti
CD3 mAb

•  Increased thymic outcome of T cells

HIV-specific immunity not restored

@Prof. Takafira MDULUZA, PhD

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Prolonged courses of continuous
HAART are not a viable option

•  Metabolic abnormalities

•  Fat redistribution

•  Mitochondriopathy

•  Liver toxicities

•  Retroviral resistance

•  Drug-drug interactions

•  Cost

@Prof. Takafira MDULUZA, PhD

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VACCINE

@Prof. Takafira MDULUZA, PhD

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 Why an HIV vaccine is possible ?

Vaccination has proven effective in other viral diseases.

Humans can regulate HIV replication partially or temporarily

Children born to HIV + mothers : some clear HIV.

Exposed uninfected individuals

Acute infection

Lon term non progressors

@Prof. Takafira MDULUZA, PhD

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