Download HIV Patho,nathis,diag - dr bujjibabu hiv clinic, vijayawada

Introduction,
Natural History
and
Pathogenesis of HIV infection
Dr.K.Bujji Babu, MD.
Consultant HIV Physician
Bujjibabu HIV Clinic
HIV/AIDS Historical Milestones
•
•
•
•
1981
1983
1984
1986
•
•
•
•
1987
1989
1991
1994
• 1996
• 1998
• 1999
First Report of AIDS, USA
Discovery of HIV
ELISA for HIV Developed
HIV-2 Identified,
HIV & AIDS Reported in India
First Antiretroviral-ZDV Approved
Screening Blood Units Mandatory
First Report of HIV-2 in India
ZDV Reduces MTCT -ACTG 076.
Protease Inhibitors Approved by FDA
Discovery of Chemokine Receptors
Short-term ZDV for MTCT CDC-Thai
Nevirapine for MTCT- HIVNET 012
Genome of HIV
Life Cycle of HIV
DS dna COMPLEX
Protease
Slide
#10
HIV Entry Mechanism
2. Co-receptor
interaction
HIV
gp41
3a. Anchorage
gp120
1. CD4
Attachment
HIV
CXCR4
CCR5
CD4
gp41
Cell
3c. Fusion
Complete
HIV
HIV 3b. coil-coil
interaction
HIV Fusion Inhibition by T-20
Source: www.trimeris.com
Molecular heterogeneity of HIV 1

Catagorized into 3 groups
group M ( major ) : subtypes or clades
A,B,C,D,F,G,H,J
:CRFs
AE,AG,AGI,AB
group O ( outlier ) :
group N
HIV-1 subtypes

SUBTYPE C PREDOMINANT

India

South Africa

Ethiopia

Botswana

Tanzania
Account for a third HIV
infections in world

SUBTYPE B PREDOMINANT

America’s

Europe

Australia & New Zealand

Japan

IDUs in Thailand, China,
Myanmar
Account for about a tenth
of HIV infections world
over.
HIV-1 Subtypes in India
HIV-1 A
HIV-1 B
Others
HIV-1 C
NARI &
other data
Differences in HIV-1 & HIV -2
• Amino Acid Homology is between 40-60%
• Majority of Infections are HIV-1 (~89%), HIV2 (2-4%) & remaining dual Reactivity in India
• Transmission by sex & MTCT less efficient
• Immunodeficiency develops slowly & milder
• NNRTI not active against HIV-2
• HIV-2 mainly present in West African nations,
prevalence rate more than 1%; now found all
over the world
Transmission of HIV

Sexual

Injection drug users

Blood and blood products

Maternal transmission

Occupational exposure
Body fluids which can transmit HIV

Blood and bloody fluids

Potentially infectious: semen, vaginal
secretions, CSF, pleural, peritoneal,
pericardial, amniotic fluid or tissue

CANNOT transmit: saliva, tears, sweat,
non bloody urine or faeces
Per-contact risk estimate for sexual
exposures with HIV+ and unprotected

Anal receptive
0.8 – 3.2%

Anal insertive
0.02 – 0.2%

Vaginal receptive
0.05 – 0.15%

Vaginal insertive
0.03 – 0.09%

Oral receptive
0.04%
Risk of transmission following
accidental needle injury

Hepatitis B virus
6 – 30%

Hepatitis C virus
0 – 7%(1.8%)

HIV
0 – 0.3%
Typical course of HIV infected person
Entry through mucosal surface/blood

Dendritic cells/macrophages

Transport to regional lymph nodes

CD4 cells infected
Characteristics of acute HIV
infection

Acute retroviral syndrome – 50-70%
cases
Fever,fatigue,rash,myalgia,pharyngitis,
lymphadenopathy,night sweats, weight
loss, candidiasis, oral ulcers etc.

High viral RNA - mean 12 million
copies/ml

CD4 counts decline, CD8 counts rise
Entry of HIV into human cells



CD4+ receptor
CCR5 and CXCR-4 receptors
Cells affected :
- CD4+ lymphocytes, naïve and memory
(latent pool)
- Macrophages/monocytes
-Tissues such as CNS, testes
Evasion of immune system control

Mutation of virus

CD8+ CTLs – deletion of initially
expanded clones due to massive viral
antigen exposure

CD8+ CTLs – segregation in the
peripheral blood

Large pool of latently infected cells that
cannot be eliminated by CD8+ CTLs
Generation of latently infected CD4+T
cells
Latently infected cells

A pool of latently infected CD4+T cells
present in all HIV individuals

Established early during the course of
primary HIV infection

Major obstacle to goal of eradication of
virus
Persistent infection

Viral latency is responsible for
persistence of HIV

HIV preferentially infects memory CD4
cells whose half-life varies from 6 to 43
months

Even in patients whose viral load < 50
copies/ml for 5 years, this is detectable

Transmission still occurs
Viral dynamics




High levels of viral replication and
destruction in plasma and lymph nodes
Almost 10 billion virions produced every
day
In primary HIV infection viral population is
relatively homogenous
Later due to rapid replication and
mutation a diverse population is produced
- quasispecies
Viral dynamics

Half life of circulating virion 30 min

Productively infected CD4 cell – 1 day

Large amount (app. 1 billion) of virus
produced and cleared form circulation
each day

HIV1 replication cycle – 1.5 days
Dynamics of HIV infection in vivo
Viral ‘Set Point’

The level of viral load after
seroconversion or virologic equilibrium
between viral replication and immunologic
containment of viral replication

Higher the set point, more rapid is
disease progression

Within the first 6-12 months of infection

Initiating antiretroviral therapy may alter
the set point
Relationship between level of virus
and rate of disease progression
Long term nonprogressors





HIV infection > 10 years, CD4 cells normal
range , stable over years and not received ART
They have low viral burden, low level of viremia
and normal immune function
No qualitative abnormalities detected in the
virus in most patients
Small subset defect in nef gene
Host factors : CCR5 – 32 deletion; CCR2 641
mutation; SDF1-3 mutation; RANTES – 28G
mutation; maximal HLA heterozygosity of class
1 loci
Mechanism of immunosuppression

Quantitative decrease in CD4+ cells

Qualitative decrease in function:
suboptimal responses to vaccines

Apoptosis

CD4+ maintained for years probably due
to repletion rather than latent virus

Decline by an average of 40-80 cells/year
without therapy
Immune responses to HIV

Activation of HIV clones of CD4 T cells
and subsequent loss

CD8 cells rapidly increase in acute
infection – kill infected cells and secrete
chemokines

Gradual failure -‘viral escape’
- HIV actually kills T cells
- decreased production
Summary

Primary HIV infection

Early/middle stages of disease – clinical
latency is not disease latency

Advanced HIV disease – CD4 < 200
cells/ml

Late-stage HIV disease – CD4 < 50
cells/ml