HISTORY OF AIDS

 1981 –
California
Several cases reported among homosexual
males, the syndrome was initially termed
'GRID' (Gay-Related Immune Deficiency)
New York
KAPOSI’S SARCOMA in similar populations
 1981: Official start of epidemic
The AIDS epidemic officially began on
June 5, 1981, when the U.S.
Centers for Disease Control and Prevention
in its Morbidity and Mortality Weekly Report
newsletter reported unusual clusters of
Pneumocystis pneumonia (PCP) caused by a
form of Pneumocystis carinii (now recognized
as a distinct species Pneumocystis jirovecii)
in five homosexual men in Los Angeles.
 August 1982
AIDS term originated.

 1983
First HIV isolated & identified

 May, 1986
HIV term coined

 Till
then 20 millions died
More than 40 millions living infected
 U.S.
Homosexuals & Intravenous drug abusers
major affected.
 Worlwide
Heterosexuals & Hemophiliacs transmission
most common.
 Africa, America & Hispanics are greatest
affected of all.
 1/3rd infected are b/w 15-24 age
 What Is HIV??
2 strains of HIV:

1. HIV 1
Most virulent & worlwide

1. HIV 2
Occur in W.Africa
now spreading to India
 HIV 1 from
chimpanzee
( Pan troglodytes)

 HIV 2 from Sooty

Mangabey
( Cercocebus atys)
 'Hunter' Theory
transference from ape to human occurred
when a human was bitten by an ape or
was cut while butchering one, and the
human became infected.
Researchers announced in May 2006 that
HIV most likely originated in wild
chimpanzees in the southeastern rain
forests of Cameroon (modern
East Province) rather than in Kinshasa,
Democratic Republic of Congo (formerly
Zaire), as had previously been believed.
Seven years of research and 1,300
chimpanzee genetic samples led
Dr. Beatrice Hahn of the
University of Alabama, Birmingham, to
identify chimpanzee communities near
Cameroon's Sanaga River as the most
likely originators.
 FROM POLIO VACCINE!!!
 OPV AIDS hypothesis, suggests that AIDS was
inadvertently caused in the late 1950s in the
Belgian Congo by Hilary Koprowski's research into a
polio vaccine.
 Edward Hooper, in his 1999 book, The River,
alleged that an experimental oral polio vaccine
prepared using chimpanzee kidney tissue was the
route through which simian immunodeficiency virus
(SIV) crossed into humans to become HIV, thus
starting the human AIDS pandemic
 This theory is contradicted by an analysis
of genetic mutation in primate lentivirus
strains that estimates the origin of the HIV-
1 strain to be around 1930, with 95%
certainty of it lying between 1910 and
1950.
 As such there is no hard evidence to
dismiss the OPV hypothesis, although
mainstream scientists consider it highly
unlikely
Since a cross species jump is most
likely the origin of HIV, and since
HIV became a true epidemic,
transmissible from human to
human, then the following
conditions were needed:
 A large human population,
 A large nearby population of the appropriate host animal,
 An infectious pathogen in the host animal, that eventually
produces a mutation that can spread from animal to
human,
 Interaction between the species to transmit enough of it
to humans to establish a human foothold, which may
take millions of individual exposures,
 A mutation of same pathogen that can spread from
human to human,
 Some method that allows the pathogen to disperse
widely. This prevents the infection from "burning out" by
either killing off its human hosts or provoking immunity in
a local population of humans.
HIV contains:

 2 identical strains of genomic RNA.

 3 Enzymes- Integrase, Protease &
Reverse Transcriptase packed in p24 &
p7/9 capsid proteins surrounded by p17
matrix protein.
 The Viral Envelope has gp120 & gp41
both attached covalently.
 gp120 has high affinity for CD4 cells (ie.
Macrophages, monocytes, dendritic cells , T-
Cells)
 Gp120 then binds to a co-receptor,
CHEMOKINE RECEPTOR, in the membrane
of the host cell before fusion & ENTRY OF
THE VIRUS.
 TROPISM in HIV:
 Macrophage tropic HIV
have Chemokine Receptors CCR5 (R5), require
low level of CD4
(Eg.macrophages, dendritic cell)
mostly spread by sexual contact .

 Lymphocyte trophic HIV

Chemokine Receptors are CXCR4 (R4), require
high CD4
 The HIV Genome
9 genes flanked by Long Terminal Repeat,
LTR
HIV CELL ENTRY
HIV LIFE CYCLE
There are 3 phases of HIV infection:

1. Acute Infection Phase/ Asymptomatic

period
2. Chronic Latent Phase
3. Crisis Phase
 1. ACUTE INFECTION/
ASYMPTOMATIC PERIOD
 2-4 weeks
 Sore throat, fever etc.
 Veremia
 Precipitous drop in no. of circulating CD4+
T cells
 Patient ‘Seroconverted’
 2. CHRONIC LATENT PHASE
 15 years ( period from HIV to AIDS)
 Low viral replication continues with decline
in CD4+ T-cells.
 A reverse CD4: CD8 ratio ( normal is 2)
 3. CRISIS PHASE
 Immunodeficient stage.

 Activation of virally infected T-cells by Ag

results in stimulation of viral transcription
and progeny form’n

 Multiple infection leads to cell necrosis.

 Drug that block HIV replication,
(protease inhibitors & viral reverse
transcriptase inhibitors) lead to a
rapid decrase in titer of infectitious
virus & an increase in CD4 T-cells

contd…………….
 Latently infected memory CD4 cells activated in
response to Ag presentation also produce virus
that can replicate in other activated CD4 T-cells.

 t1/2of latently infected CD4 T-cells is more than

49 months…

 Macrophages & dendritic cell seem to act as

reservoir of replicating virus & also spreading
agents to other tissues ( brain, kidney etc.)
SEROCONVERSION IS THE CLEAREST
EVIDENCE FOR AN ADAPTIVE IMMUNE
RESPONSE TO INFECTION WITH
HIV…..

contd……….
 2 group of people are made on
their Sero-Activity:
 SERO+ people
They make Ab’s against HIV protein but don’t seem to have
progressive disease.
Their CD4 T-cell counts are also maintained.

 SERO- people
They are highly exposed to HIV, yet remain disease-free & virus-
negative.

 Some has specific cytotoxic lymphocyte & TH 1 lymphocytes

directed against infected cells
CONTROL OF HIV-INFECTED CELLS
BY CD8 CYTOTOXIC T-CELLS

 In vitro, T cells from infected individuals had shown to kill

infected cells

 In vivo, T cells can be seen to invade sites of HIV

replication.

 Patients with high levels of CD8 T cells showed slower

progression of disease.

 Direct evidence from experiments in macaques infected

with SIV ( Simian immunodeficiency virus) in vivo.
 Some people carry mutant alleles on
their cell-surface chemokine receptors
 Some Gambian & Kenyan Sex-Workers exposed
to many HIV-infected males each month upto 5
years were found to lack Ab responses but
cytotoxic T-lymphocytes responsesto peptide
epitopesof HIV.

But, they don’t hav any mutant allele. Only 10%

subsequently acquired HIV infection.

However, after reduced sex-work, HIV

infection was found more frequentlu
 …..The 1st promising drug for AIDS
 Acts in 3 steps:
1. Nucleoside inhibitor of reverse
transcriptase
2. Protease inhibitor
3. Therapeautic agents

 Drug resistance deveoped rapidly in just

3 or 4 viral mutations.
 - Highly Active Anti-Retroviral Therapy/

2 of the inhibitors are against reverse

transcriptase & protease.
 Hoped to delay the mutation of the virus.
 Prevents infection of new cells, previosly
infected cells remain until lysed.

 Has many SIDE-EFFECTS.

 Costs $20,000/year.
 Failedin the Rhesus Monkey…
 Works on progress
 Rapid replication of HIV
109 – 1010 virions/day

 Very High Mutation Rate:

3 X 10-5 per nucleotide base/ cycle of
replication. Hence many variants in a
single day.
 Vaccines from envelope protein gp120
has been tested on chimpanzee…
But, failed as it had very precise action.
 Very long period of LATENCY or WINDOW period during
which HIV is undetectable in human blood.

 Latently infected memory CD4 cells activated in response

to Ag presentation also produce virus that can replicate in
other activated CD4 T-cells.

 t1/2 of latently infected CD4 T-cells is more than 49

months…

 Macrophages & dendritic cell seem to act as reservoir of

replicating virus & also spreading agents to other tissues
( brain, kidney etc.)
 KilledHIV-1 doesn’t retain antigenecity
 Live attunated retrovirus possess safety
issues.
 Nosuitable animal model for HIV/AIDS at
present.
Human models raises ethical issues.