Acute HIV Infection Translating Pathogenesis into Opportunity

1. Acute HIV InfectionTranslating 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 3rd 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 QuestionMGH-NCSU collaboration Should this individual be treated with antiretroviral therapy??

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

9. Should individuals with Acute HIV-1 infection be treated with antiretroviral therapy? ? ? ? ? ? Kassutto et al, CID 2006

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

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

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

13. Host genetic factors Viral factors Host immune responses

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

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

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

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

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

19. Critical relationship between CD4 and CD8

20. Opportunity #1Rescue 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. CD4 cells Activation & Expansion Infection Impairment Class II TCR CD4

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

23. Kassuttoet al, CID 2006

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

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 immunitySTI Hypothesis RX RX RX RX CTL Th Magnitude Viral Load Time

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 2000Kaufmann 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. AC-10 (1.5 years on therapy) HIV-1 RNA Autol Nab 1000 6000 5000 100 4000 Plasma HIV-1 RNA 3000 Neutralizing antibody titer 10 2000 1000 1 0 0 50 100 150 200 250 Montefiori, J Virology 2001 Days off therapy

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

37. AC-06 150000 8.8 x 106 100000 50000 < 50 24 months 36 months 48 months 12 months

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

39. 31 45 243 226 VRHFPRIWLHGLGQH WRKLVDFRELNKRTQDFW 295 309 242 259 NCTRPNNNTRKSIHI FWEVQLGIPHPAGLKKK 766 780 308 322 FSYRRLRDLLLIAAR WKGSPAIFQSSMTKI 842 856 423 437 HIPRRIRQGLERALL SQIYPGIKVRQLCKL 521 65 504 79 LKTGKYARMRGAHTNDVK EVGFPVTPQVLRPM 894 911 75 89 vpr AVFIHNFKRKGGIGGYSA PLRPMTYKAAVDLSH vpu vif 5562 5853 pol nef 6302 5044 5622 6070 gag env 5099 8807 2088 9431 793 2295 6230 8805 TACQGVGGPGHKAPVL 631 tat 1 363 348 5834 6048 8368 8458 HPVHAGPIAPGQMREPR rev 216 232 5973 6048 8368 8663 GATPQDLNTMLNTV 178 191 ERILSTYLGRSAEPV 57 71 SPRTLNAWVKVVEEK 148 162 KKTKPPLPSVKKLT 170 157 WEKIRLRPGGKKKYK 16 30 THPRVSSEVHIPLG RRQDILDLWIYHTQG 47 60 119 105 KSLVKHHMYISKKAK TYKSSVDLSHFLKEK 80 94 22 36 VTPQVPLRPMTYKAA QVDRMRIRTWKSLVK 26 70 84 12

40. AC-06 150000 8.8 x 106 100000 50000 < 50 24 months 36 months 48 months 12 months

41. AC-06 150000 8.8 x 106 100000 50000 < 50 24 months 36 months 48 months 12 months

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

43. Immune escape in anchor residues F V S N L T A Y T HLA Class I molecule

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.