HIV Pathogenesis

1. HIV Pathogenesis Jay Ravishankar M.D. jravishankar@downstate.edu 718 270 4180 10/14/08

2. HIV pathogenesis • Natural History of HIV infection Stages of HIV –1 infection • Viral transmission, primary HIV infection, seroconversion, clinical latent period, early symptomatic infection, AIDS, Advanced HIV. • Treatment

3. Window period EIA / WB Elite Controllers. M tropic virus CD4 < 50 A. HIV of 8-10yrs, CD4 > 500, VL < 50 no ART, B. CCR5 receptor C. CMV and atypical mycobacteria E. 6-12 weeks F. Detects antibodies Match the following

4. Natural History of HIV Infection

5. Primary Infection

6. HIV most often enters thru the genital mucosa HIV has several targets including dendritic cells, macrophages, and CD4+ T cells Clinical infection is more commonly mediated by macrophage (M tropic) rather than T cell tropic viruses The viral envelope protein gp 120 binds to the CD4 molecule on the dendritic cell Vaginal acquisition of HIV infection.

7. Viral entry into the human cell

8. CCR5 - Used by R5 HIV-1 • Macrophage tropic, NSI, slow replicating • Transmitted, persists throughout infection • CXCR4 - Used by X4 HIV-1 • T-cell line tropic, SI, Fast replication • Associated with accelerated CD4 T cell lost

9. ↑ X4 R5 Mixed/Dual CXCR4-tropic HIV Dual-tropic HIV Immune function Limit of tropism assay detection* Amount of virus CCR5-tropic HIV Time * Detects upto 0.3% of a tropism with current enhanced tropism assay HIV Tropism and Disease Progression Courtesy GSK interactive CD "Exploring an allosteric world: CCR5 entry inhibitors and HIV"

10. Within 2 days of exposure HIV is detectable in regional lymph nodes In plasma within 5 days Once virus enters the blood, there is widespread dissemination to organs such as the brain, spleen, and lymph nodes Primary HIV infection

11. Human cells susceptible to HIV infection

12. Target Cells in HIV Infection

13. T cell dynamics in primary/acute infection • One of the most notable immunologic defects in HIV-1 infection is the relatively weak or absent HIV-1-specific T helper cell function seen in most infected individuals • HIV differs from other chronic viral infections in that the virus selectively targets and infects activated, expanding CD4 T cells • During acute infection, viral replication occurs at an extremely rapid rate. • Rapidly proliferating virus-specific TH become activated and expand in the presence of high viremia, resulting in subsequent infection and destruction of these cells. • The progressive loss of CD4 cells is a hallmark of this disease

14. Mechanisms of CD4 cell loss in HIV infection Syncytium Virus mediated Apoptosis CTL induced

17. Viral Dynamics/Kinetics • High rates of viral replication • 10 billion new HIV particles daily • Rapid replication + low fidelity of the replication process • Allows HIV to mutate rapidly into a population of genetic variants called Quasi species. • Allows evolution of HIV with increasing virulence • Is the cornerstone of rapid development of resistance to antiretroviral drugs. • Complete suppression of HIV replication may help to prevent disease progression.

18. Biochemical markers in primary HIV infection Antibodies Viral load CD4

19. Viral RNA Envelope antibodies P24

20. Screening EIA (in pair) followed by confirmatory WB Neg no bands Positive –gp120/160 and either P24 or gp41 Indeterminate –presence of any other bands Sensitivity and specificity >99.5% in established disease Window Period-6-12 weeks Standard test for HIV

21. Rapid HIV test

22. HIV RNA Levels: Viral Load Assays • Viral load blood test measures • # copies HIV RNA particles / mL plasma • Primary infection • HIV RNA becomes detectable and rises to a peak, then • Tapers to a stable level - “virologic set point”. • Virologic set point is different in different individuals and its magnitude is predictive of the risk of disease progression.

23. HIV RNA Levels: Viral Load Assays(cont’d) • F.D.A. approved for prognosis • Determining the risk of progression of HIV disease to AIDS and death and therefore, • Determining the need for antiretroviral therapy and • Therapeutic monitoring of the effectiveness of antiretroviral therapy. • Unacceptably high false-positive rate • Not approved for diagnosis of HIV infection nor serologic surveillance.

24. LABORATORY MARKERS OF HIV INFECTION Markers of Immunologic Damage by HIV a. Subsets of T lymphocytes 1) measured by flow cytometry with 2) fluorescence-labeled monoclonal antibodies to 3) functional surface proteins (CD4 and CD8) 4) Normal Values Helper / CD4 + cell count = 400-1200 Suppressor/ CD8 + cell count = 400-800

25. Acute HIV Infection • Many patients experience an acute syndrome within days to weeks of primary HIV infection. • Often dismissed as self-limited viral syndrome resembling mononucleosis • In one study, symptoms that occurred in more than ½ of patients presenting with acute HIV infection included Fever (88%), Malaise (72%), Myalgia (60%), Morbilliform rash (58%), Headache (55%), Night sweats (50%). • One symptom that was a negative predictor of HIV infection, nasal congestion, occurred in 18% of patients with acute HIV infection compared with 38% of patients without acute HIV infection (Daar ES, et al. Ann Intern Med 2001; 134:25-29) • The take home message is that all patients with any risk factor for HIV infection should be offered testing whenever they present with the symptoms listed above.

28. Clinical Latency

29. CTL CD4 Viral RNA

30. Middle Stage of HIV infection(Clinical latency) • Begins with establishment of the virologic set point (months after initial infection) • Ends with signs of severe immune system compromise (years after initial infection) • AIDS diagnosis- development of an opportunistic infection, or risk of opportunistic infection= CD4 count <200/cc) • In absence of therapy, median duration is approximately 8-10 years, although there is wide variation in rate of progression. • Destruction of lymphoid tissue may occur even at low viral loads • Women appear to progress at lower HIV viral loads than men. • Clinical manifestations are usually minimal early in this stage with the exception of lymphadenopathy, which in some patients, regresses as the disease progresses. (Clinical latency)

31. Middle Stage of HIV Infection(Clinical Latency cont’d) • Episodic conditions that can occur include herpes zoster, oral or vaginal candidiasis, pneumonia and reactivation of tuberculosis. • Serve as clinical clues to perform HIV testing if a person presents with these conditions and has not yet been tested for HIV. • A common laboratory abnormality is hypergammaglobulinemia. Prior to 1985, this was a surrogate marker for HIV infection before an antibody test was developed. • Hint, another indication to offer HIV testing, when this is the only lab abnormality found during a work-up.

33. Likelihood of Developing AIDS in 3 Yrs CD4+ cells/µL Percent progressing >30,000 10,000- 3,000- 501- <500 30,000 10,000 3,000 Plasma HIV RNA (copies/mL) Adapted from: Mellors J et al. Ann Intern Med. 1997.

37. Advanced HIV Disease • CD4+ count < 200 cells/mm3, but no Opportunistic Infections • In absence of prophylaxis, infections such as Pneumocystis carinii pneumonia (PCP), cerebral toxoplasmosis, and other infections can occur. • Some patients remain asymptomatic (clinical latency). • Without proactive counseling and testing programs, this is when most patients will present for care.

40. Late Stage HIV Infection • CD4 count < 50 cells/mm3 • High risk of atypical Mycobacterial infections (Mycobacteriaaviumintracellulare, etc.), cytomegalovirus infection, PML can occur • Secondary symptoms such as anorexia, diarrhea and wasting (Slim disease). • High risk of death.

41. Factors Affecting HIV Disease Progression • Age: people older than 35 yrs progress to AIDS faster than 16-24 yrs 6 :15 (Am J of epidemiology 1992) • Pts who have symptomatic primary infection tend to progress rapidly than asymptomatic at seroconversion. • Replicative capacity of the virus • CCR5 co receptor usage VS CXCR4 • CCR5 Δ 32 heterozygosity associated with decreased risk of progression

42. Risk of progression Co infection with other pathogens • Herpes • Syphilis • Super infection with HIV • TB Impact of treatment

43. CD4>500 HIV>13yrs No HAART Also called controllers VL<50 elite controllers

44. Interval summary • HIV pathogenesis—Depletion of CD4 T cells. • Biochemical markers ( antibodies, VL, CD4) of HIV infection • Symptoms of primary infection • Clinical latency period • Advanced disease

45. Interventions • Prophylaxis against Opportunistic Infections Antimicrobials used to prevent infections caused by pneumocystis carinii, atypical mycobacterial infections, • Treatment of HIV infection

47. Antiretroviral Drug Approval:1987 - 2008 RAL MVC ENF ATV FTC FPV ETR Pre HAART ERA Monotherapy Sequential adding Resistance TPV DRV TDF EFV ABC LPV/r APV RTV IDV NVP NFV DLV 3TC SQV d4T ddC AZT ddI

48. Nucleoside/nucleotide RTI Non-nucleoside RTI Protease inhibitors AZT-Retrovir Viramune Invirase ddi-Videx EC Rescriptor Norvir Hivid Sustiva Crixivan Viracept D4t-Zerit 3TC-Epivir Agenerase Kaletra Abacavir-Ziagen Tenofovir-Viread Reyataz Selzentry Integrase Inhibitor Entry/fusion inhibitors N(t)RTI/NNRTICombinations Lexiva FTC-Emtriva Aptivus Prezista Combivir Isentress Trizivir Fuzeon Atripla Epzicom Truvada FDA-Approved Antiretroviral Agents Intelence

49. A 40 yr male was diagnosed with HIV infection 2 weeks ago. His CD4 is 247 and VL 55,000. • He is willing to be engaged in medical care. • What do you do?

50. When to start treatment? Eradication of HIV Infection is not possible