HIV Basics: Pathogenesis

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1 HIV Basics: Pathogenesis Michael Saag, MD, FIDSA University of Alabama, Birmingham Director, Center for AIDS Research ACTHIV 2011: A State-of-the-Science Conference for Frontline Health Professionals

Learning Objectives Upon completion of this presentation, learners should be able to: Appraise where antiretroviral drugs work and how the mechanism

2 Learning Objectives Upon completion of this presentation, learners should be able to: Appraise where antiretroviral drugs work and how the mechanism of action translates into drug efficacy and drug resistance Assess how pathogenesis concepts impact HIV policy, including the National AIDS Strategy

3 What is a retrovirus? It is a virus that: 1. Was discovered in the 60 s during the counter-culture revolution 2. Set mankind back by 50 years 3. Plays records backwards 4. Transcribes RNA into DNA 5. All of the above

4 HIV originated in: 1. Dogs in South Africa 2. Monkeys in Zanzabar 3. Chimpanzees in Cameroon 4. Leopards in Liberia 5. Gays in the Military

5 Magdalena Lukasik (JGI)

6 Martin Muller

7 SIVcpz in wild chimpanzees P. t. verus P. t. vellerosus P. t. troglodytes P. t. schweinfurthii Dja Tai * Goualougo Kisangani * * Budongo Kibale Nyungwe Gombe Mahale Hahn, et al, Nature, 2002

8 M. Worobey, 2007 HIV/SIV Nomenclature

9 23 yo Male A case: WEAU 3 days of fever, myalgias, anorexia, diarrhea, and sore throat Exam Febrile, Skin rash, pharnygeal erythema, lymphadenopathy Lab WBC 2,300 43% lymphs, 12% mono, 45% polys Monospot / HIV EIA / WB: Negative

11 Which of the following is the most likely diagnosis 1. Mononucleosis (EBV) 2. CMV infection 3. Toxoplasma gondii infection 4. HIV infection 5. Group A Streptococcal infection

12 Natural History and Laboratory Staging of HIV Infection Eclipse Phase I II III IV V VI v RNA+ (Fiebig, AIDS 2003) Western blot +/- Western blot + (p31-) Western + (p31+) Keele et al., PNAS 2008

13 Productive Infection by a Single Virus Sequences compared to Consensus PRB956 59% identical to Consensus Keele et al., PNAS 2008

14 Productive Infection by Two Viruses Sequences compared to Consensus SC33 Keele et al., PNAS % identical to consensus A 57% identical to consensus B

15 HIV-1 Transmission Model Donor Mucosa Recipient Abortive Abortive Abortive Abortive Time (days) Conclusion: The consensus env sequence at peak viremia most often corresponds to the env sequence of the transmitted virus (Keele et al., PNAS 2008).

16 Keele et al., PNAS 2008

17 CD4+ T Cells Natural History of Untreated HIV Disease HIV RNA (log) Time after Infection

18 Pro-inflammatory aspects of HIV (which is unique to this virus) results in continuous activation and turnover of CD4+ and CD8+ T cells, leading to eventual immunologic exhaustion SG Deeks, MD. Presented at IAS USA Atlanta Course, March 11, Grrossman et al, Nature Med 2002

19 HIV replicates in: 1. The bloodstream 2. Semen 3. Lymphatic tissue 4. Urine 5. Your mind

Terminal ileum, HIV uninfected Terminal ileum, Week 3 HIV Infection HIV infection results in a rapid and dramatic depletion of CCR5+ CD4+ memory T cells in

20 Terminal ileum, HIV uninfected Terminal ileum, Week 3 HIV Infection HIV infection results in a rapid and dramatic depletion of CCR5+ CD4+ memory T cells in gut (without evidence of increase activation/turnover) SG Deeks, MD. Presented at IAS USA Atlanta Course, March 11, Brenchley et al; J. Exp. Med 2004

21 CD4 + T Cell Decline (cells/µl/year) Relationship between viral load and rate of CD4+ T cell decline among untreated patients 60 (n=2005) R 2 = 0.06, P < < 500 (n=217) (n=285) ,000 (n=501) ,000 (n=501) Baseline Plasma HIV RNA Level SG Deeks, MD. Presented at IAS USA Atlanta Course, March 11, >60000 (n=501) Rodriguez, Lederman; CROI 2005

22 M Saag, UAB

23 The insertion of viral provirus into the host DNA: 1. Can cause malignant transformation of the host cell 2. Can induce cell-death of the cell 3. Can lead to development of a stem cell 4. Has no effect on the cell 5. Really pisses the cell off

25 Viral Load Latently Infected CD4+ Lymphocytes T 1/2 = 1.1 days HIV Infected Cells HIV virions Weeks Antiretroviral Rx Uninfected Activated CD4+ Lymphocytes M Saag, UAB Uninfected Resting CD4+ Lymphocytes

26 RNA+ cells in Lymph node vs RNA in Plasma Plasma Viral Load (copies/ml) < HIV RNA+ cells/10 6 LN cells Hockett et al, J Exp Med, 1999

27 At steady state, when an actively producing cell dies, it is replaced by how many newly infected cells? 1. One 2. Twenty Five 3. One Hundred 4. One Thousand 5. It depends on the viral load

28 M Saag, UAB

29 VL = 100,000

30 VL < 50

36 Viral Load T 1/2 = 1.1 days Weeks Wei et al, Nature, 1995

37 Relative Time on Treatment 40 years on Rx CD4 650/ul 35 years on Rx 5 years CD4 500/ul AGE (years)

38 Relative Time on Treatment 40 years on Rx CD4 650/ul 5 years HARM? 35 years on Rx CD4 500/ul AGE (years)

39 So.what is the harm? (Pick the most compelling reason) 1. Destruction of Lymphoid Tissue 2. Inflammation 3. Increased Cardiovascular Events 4. Increased incidence of certain malignancies 5. Increased Aging 6. Accelerated Cognitive Decline

40 Goals of Antiretroviral Therapy Prevent Clinical Progression Prevent Resistance

43 Does treating HIV lead to reduced transmission of HIV? 1. Yes 2. No 3. Depends on the sexual practices!

Aware of Infection account for ~54% New Infections

44 Most New Infections Transmitted by Persons who Do Not Know Their Status ~25% Unaware of Infection ~75% Aware of Infection account for ~54% New Infections ~46% of New Infections Source: G. Marks et al. AIDS 2006

45 TNT: Based on the association of viral load and HIV transmission risk Transmission rate per 100 Person-Years < > < > < > All subjects Male-to-Female Transmission Female-to-Male Transmission 0 Viral load (HIV-1 RNA copies/ml) and HIV transmission Quinn TC, et al. NEJM 2000; also Fideli U, et al. AIDS Res Hum Retrovir 2001

46 Thanks UAB 1917 Clinic Cohort supported by UAB CFAR (grant P30-AI27767), CNICS (grant 1 R24-AI ), and the Mary Fisher CARE Fund

The how and why of Acute HIV Infection 1. How do we best diagnosis patients with acute HIV?

Acute HIV infection Eric Rosenberg, MD Associate Professor of Pathology Director, Clinical Microbiology Laboratory Massachusetts General Hospital Harvard Medical School The how and why of Acute HIV Infection