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

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

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)

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

Diagnosis Acute HIV infection

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

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

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?

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

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

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

Viral factors Host immune responses Host genetic factors

New virus assembly Humoral immune response Neutralizing Antibodies B cell

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

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

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

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

Critical relationship between CD4 and CD8

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

Activation & Expansion ImpairmentInfectionCD4 cells Class II CD4 TCR

Activation & Expansion Antiretroviral therapyCD4 cells Class II CD4 TCR

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

controlchronicacute LTNP Rx No Rx Stimulation index Rosenberg et al, Science 1997 Spontaneously control virus

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

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

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

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

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?

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

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

AC-02 STI cycle #1

AC-02 STI cycle #2

HIV-1 RNA Autol Nab AC-10 (1.5 years on therapy) Days off therapy Neutralizing antibody titer Plasma HIV-1 RNA Montefiori, J Virology 2001

1h 2h 5j 6e Jrfl Hxb2 NL43 2b a 1c 1b 2c 1d g 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 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

AC x 10 6 < months 24 months36 months48 months

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

AC x 10 6 < months 24 months36 months48 months

AC x 10 6 < months 24 months36 months48 months

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

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

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

Presence of Two Distinct Viruses Altfeld et al, Nature

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

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.