Introduction,Natural History

andPathogenesis of HIV infection

Dr.K.Bujji Babu, MD.

Consultant HIV Physician

Bujjibabu HIV Clinic

HIV/AIDS Historical Milestones• 1981 First Report of AIDS, USA

• 1983 Discovery of HIV

• 1984 ELISA for HIV Developed

• 1986 HIV-2 Identified, HIV & AIDS Reported in India

• 1987 First Antiretroviral-ZDV Approved

• 1989 Screening Blood Units Mandatory

• 1991 First Report of HIV-2 in India

• 1994 ZDV Reduces MTCT -ACTG 076. Protease Inhibitors Approved by

FDA

• 1996 Discovery of Chemokine Receptors• 1998 Short-term ZDV for MTCT CDC-Thai

• 1999 Nevirapine for MTCT- HIVNET 012

The Human Immunodeficiency Virus

Genome of HIV

Life Cycle of HIV

DS dna COMPLEX

Protease

HIV Entry Mechanism

3c. FusionComplete

1. CD4Attachment

3b. coil-coilinteraction

CXCR4CCR5

HIV

HIV

gp120

3a. Anchorage

CD4

2. Co-receptorinteraction

Cell

HIV

HIV

HIV

gp41

gp41

HIV

Slide #10

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 C

HIV-1 AHIV-1 B

Others

NARI & other data

Differences in HIV-1 & HIV -2

• Amino Acid Homology is between 40-60%

• Majority of Infections are HIV-1 (~89%), HIV-2 (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