1. Introduction, Natural History and Pathogenesis of HIV infection Dr.K.Bujji Babu, MD. Consultant HIV Physician Bujjibabu HIV Clinic

2. HIV/AIDS Historical Milestones 1981First Report of AIDS, USA 1983Discovery of HIV 1984ELISA for HIV Developed 1986HIV-2 Identified, HIV & AIDS Reported in India 1987First Antiretroviral-ZDV Approved 1989Screening Blood Units Mandatory 1991First Report of HIV-2 in India 1994ZDV Reduces MTCT - ACTG 076. Protease Inhibitors Approved by FDA 1996Discovery of Chemokine Receptors 1998Short-term ZDV for MTCT CDC-Thai 1999 Nevirapine for MTCT- HIVNET 012

5. Genome of HIV

8. Life Cycle of HIV DS dna COMPLEX Protease

10. HIV Entry Mechanism 3c. Fusion Complete 1. CD4 Attachment 3b. coil-coil interaction CXCR4 CCR5 HIV gp120 3a. Anchorage CD4 2. Co-receptor interaction Cell HIV gp41 HIV Slide #10

11. HIV Fusion Inhibition by T-20 Source: www.trimeris.com

12. 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

13. 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.

14. HIV-1 Subtypes in India NARI & other data

15. 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

16. Transmission of HIV  Sexual  Injection drug users  Blood and blood products  Maternal transmission  Occupational exposure

17. 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

18. 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%

19. Risk of transmission following accidental needle injury  Hepatitis B virus 6 – 30%  Hepatitis C virus 0 – 7%(1.8%)  HIV 0 – 0.3%

20. Typical course of HIV infected person

21. Entry through mucosal surface/blood  Dendritic cells/macrophages  Transport to regional lymph nodes  CD4 cells infected

23. 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

24. 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

25. 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

26. Generation of latently infected CD4+T cells

27. 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

28. 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

29. 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

30. 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

31. Dynamics of HIV infection in vivo

32. 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

33. Relationship between level of virus and rate of disease progression

35. 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

36. 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

37. 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

38. 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