1. Acute HIV Infection Translating Pathogenesis into Opportunity Eric S. Rosenberg, M.D. Associate Professor of Medicine Massachusetts General Hospital Harvard Medical School erosenberg1@partners.org

2. 47 year old male Present to MGH ED with an 8 day history of : Fever to 102.5 Headache Photophobia Myalgias and arthralgias Nausea and vomiting 3 rd visit to health care system

3. 47 year old male Additional history: Recent unprotected sex with an HIV infected partner PMH: prior history of syphilis Exam: Fever Cervical lymphadenopathy Rash (started on torso spread to limbs and scalp)

5. 47 year old male Diagnostics: Test for EBV, CMV, influenza were negative HIV ELISA Negative Western Blot negative (no bands) HIV RNA > 750,000 copies/ml 1:100 dilution 47,000,000 copies/ml CD4 count = 432 cells

6. Diagnosis Acute HIV infection

7. Framing the Question MGH-NCSU collaboration Should this individual be treated with antiretroviral therapy??

8. Acute HIV infection Goals 1.To discuss the advantages and disadvantages of treating individuals with acute HIV 2.To review the early biological events of acute HIV infection 3.To review the immunologic rationale for treatment during acute infection and possible treatment interruption

9. AdvantagesDisadvantages Preservation of HIV-specific cellular immune responses Toxicities and unknown long- term risks Opportunity for structured treatment interruption Short- and long-term clinical benefits are not well-defined Lowering of HIV-1 set pointResistance acquisition Limitation of viral evolution and diversity Limitation of future antiretroviral therapy options Decreased transmissionQuality of life impact Mitigation of acute retroviral symptoms Cost ? ? ? ? ? Kassutto et al, CID 2006 Should individuals with Acute HIV-1 infection be treated with antiretroviral therapy?

10. HIV infection J. Coffin, XI International Conf. on AIDS, Vancouver, 1996 Viral Load = Speed of the train CD4 count = Distance from cliff Antiviral therapy/host immune response = Brakes Understanding the terminology and variables that can be measured

11. The Dynamics of Acute HIV Infection HIV Viral Load 6-12 months Rapid Progression Slow Progression 28, 240 59, 987 11,843 Interquartile ranges Lyles et al, 2000 CTL HIV Ab 2-8 weeks

12. Since the level of HIV in the blood predicts progression, What factors influence viral replication?

13. Viral factors Host immune responses Host genetic factors

14. New virus assembly Humoral immune response Neutralizing Antibodies B cell

15. Viral debris Rapid evolution and diversification of HIV (horse is already out of the barn) Inadequate T cell “help” Why do neutralizing antibodies fail?

16. New virus assembly 2-3 Days CTL Soluble factors Cellular Immune Responses

17. If CTL are present, why is the immune response not more effective in HIV infection?

18. Antigen Presenting Cell Class II CD4+ Th Cell CD4 HIV-Specific T Helper Cells are impaired in all stages of disease TCR 1. Activation 2. Clonal expansion 3. Cytokine secretion

19. Critical relationship between CD4 and CD8

20. Opportunity #1 Rescue of HIV-specific T helper cells Hypothesis (pathogenesis): HIV-specific T helper cell (CD4) responses are impaired during acute infection Hypothesis (opportunity): Treatment with ARV during acute infection will protect these responses from being lost

21. Activation & Expansion ImpairmentInfectionCD4 cells Class II CD4 TCR

22. Activation & Expansion Antiretroviral therapyCD4 cells Class II CD4 TCR

23. Characteristic AcuteEarly total n Median age (years) [IQR] 35 [31,39] 37 [34,43] 102 Male gender (%)94 102 HIV Risk Factor MSM (%) 828194 White race (%)7778102 Mean baseline VL (copies/mL) (range) 5.61 million (11,000-95 million) 382,000 (2800-2.95 million) 75 Mean baseline CD4 (cells/mm 3 ) (range) 445 (42-1093) 567 (170-981) 100 Kassutto et al, CID 2006

24. controlchronicacute LTNP 1 10 100 1000 Rx No Rx Stimulation index Rosenberg et al, Science 1997 Spontaneously control virus

25. Observation Immune damage occurs in the earliest stages of acute HIV infection, but there appears to be a “window of opportunity” to reverse this damage with treatment

26. Opportunity #2 Can treatment be initiated during acute HIV infection and then discontinued?

27. Lessons from Berlin Lisziewicz et al, NEJM 340 (21), 1999

28. Augment HIV-specific immunity STI Hypothesis RX RX RX RX Time Magnitude CTL Th Th Viral Load

29. Can therapy be discontinued? Will HIV-1-specific immune responses generated and maintained during acute infection be enough to control viremia? If virus returns once therapy is discontinued, can this “snap-shot” of autologous virus further boost the immune system?

30. Structured treatment interruption Several patterns have emerged Failure Transient control of viremia with sudden loss of containment Control (durability?) Rosenberg et al, Nature 2000 Kaufmann et al, PLoS Med 2004

31. Opportunity #3 There is more translating to do… Each patient tells a different story

32. AC-02 STI cycle #1

33. AC-02 STI cycle #2

35. 050100150200250 1 10 100 1000 HIV-1 RNA 0 1000 2000 3000 4000 5000 6000 Autol Nab AC-10 (1.5 years on therapy) Days off therapy Neutralizing antibody titer Plasma HIV-1 RNA Montefiori, J Virology 2001

36. 1h 2h 5j 6e Jrfl Hxb2 NL43 2b 100 89-6 1a 1c 1b 2c 1d 100 77 5g 6h 5a 6c 5e 3a 6m 2f 1k 1l 6i 5c 3e 5b 5h 2k 6l 5d 1b 3b 3h 4a 5k 2e 6d 10 3d 3g 6f 2b 2i 1m 1j 1i 6g 6j 6k 1a 3f 1n 5m 5f 6n 1e 2c 3c 2d 5i 5n 4b 2a 1d 2g 1c 2j 1f 5l 1g 6b 5o 99 96 99 97 Chronic pt. Acute pt. 1a 1b 1c 1d 1e 1f 1g 2a 2b 2c 2d 2h 2f What is unique about treated acute infection? Lack of viral diversification

37. AC-06 50000 100000 150000 8.8 x 10 6 < 50 12 months 24 months36 months48 months

38. New virus assembly 2-3 Days CTL Soluble factors Cellular Immune Responses

40. AC-06 50000 100000 150000 8.8 x 10 6 < 50 12 months 24 months36 months48 months

41. AC-06 50000 100000 150000 8.8 x 10 6 < 50 12 months 24 months36 months48 months

42. N T V A T L Y L S Viral peptide in HLA Binding Groove HLA Class I molecule

43. N Y F S T V T A L Immune escape in anchor residues

44. Viral Variation in Gag KIRLRPGGK-A03 RLRPGGKKKY-A03 Day 18 MGARASVLSGGELDKWEKIRLRPGGKKKYRLKHIVWASRELERFALNPSLLETSGGCRQILGQLQPSLQTGSEELKSLFNTIAVLYCVHQRIDVKDTKEA> Day 1170..........................T.K...............V..G............K..H.............Y..V.T........EIR.....> SPRTLNAWV-B07 TPQDLNTML-B07 Day 18 LDKIEEEQNKTKKKAQQAAADTGNSSQVSQNYPIVQNLQGQMVHQPISPRTLNAWVKVVEEKAFSPEVIPMFTALSEGATPQDLNTMLNTVGGHQAAMQM> Day 1170.........C..RE..............................S..........................S...........................> HPVHAGPIA-B07 Day 18 LKETINEEAAEWDRLHPVHAGPIAPGQMREPRGSDIAGTTSTLQEQIAWMTNNPPIPVGDIYKRWIILGLNKIVRMYSPSSILDIKQGPKEPFRDYVDRF> Day 1170.............M.......V........................Q...S...V...E...................T....................> GPGHKARVL-B07 Day 18 YKTLRAEQASQDVKNWMTETLLVQNSNPDCKTILKALGPAATLEEMMTACQGVGGPGHKARVLAEAMSQMTSPANIMMQRGNFKNQRKIVKCFNCGKEGH> Day 1170..........E..G..........A.............G.............................V.NS.T........R....T...........> Day 18 IARNCRAPRKKGCWKCGQEGHQMKDCTERQANFLGKIWPSHKGRPGNFLQSRPEPTAPPAESLMFGEETTTPPQKQEPRDKELYPPLASLRSLFGNDPSSQ> Day1170...........................................................E..VR.....A..S...GTI......-...............> Altfeld et al, Nature

45. Presence of Two Distinct Viruses Altfeld et al, Nature

46. Is the “possibility” of STI enough reason to treat individuals during acute HIV infection? Enough question exists regarding the use of STI as a management strategy that the most relevant question in 2008 is whether or not to treat during acute infection

47. Conclusions It is not known whether treatment during acute infection is the correct thing to do STI may have a role in management of individuals treated during acute infection but optimal approach not known. Mathematical and statistical modeling (NCSU- MGH) to inform the design of the first randomized trial of treatment versus no treatment during acute HIV.