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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