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New Insights into the Immune Response and Viral Reservoir During AHI
Lydie Trautmann, EngD, PhD Cellular Immunology Section U.S. Military HIV Research Program Walter Reed Army Institute of Research
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No conflicts of interest to declare
Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense. The investigators have adhered to the policies for protection of human subjects as prescribed in AR 70–25.
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Why is Acute HIV Infection Important?
Tissue infection CD4 depletion More cells are infected Exhausted immune system Mutated HIV evades immunity Plasma Viral RNA (copies per ml) Days following HIV-1 Transmission The first 4 weeks of infection In the days following HIV transmission, the immune system is not able to control HIV replication. All the immunological events occurring in the first weeks of infection are important to understand as this host pathogen interaction determines disease progression during chronic infection and even after ART. CD4 T cells are infected and as they fuel the infection, they get depleted from tissues leading to systemic inflammation. Eventually, as the immune system tries to control the viral replication for weeks and is exposed to high levels of antigen, it becomes exhausted, with HIV-specific T cells expression of immune checkpoint blockers. Several studies characterized the immune responses against the virus in AHI and showed that after only a few weeks of untreated infection, the virus evades the immune pressure. The acute HIV infection is divided in stages of few days each with stage 1 and 2 prior to peak viremia, and stage 3 corresponding to peak viremia. Very few studies have looked at the immune responses in the earliest stages of AHI. Chronic infection AHI Fiebig I II III IV V VI McMichael Nat Rev Immunol 2010; Fiebig AIDS 2003
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CD8 T Cells in AHI Impact Viral Set Point
Recently, the impact of immunity was analyzed in the FRESH cohort in South Africa were women at high risk are followed and diagnosed within days of HIV infection. The activated CD8 T cells increasing in AHI were predominantly HIV-1 specific and followed viremia as previously reported. Importantly, the frequency of these HIV-specific CD8 T cells at their peak were inversely correlated with setpoint viral load and the rapidity of these responses to rise to their maximum level was also correlated with viral load setpoint suggesting that strong and rapid responses agains the virus lead to a better control. Ndhlovu et al, Immunity 2015
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Days Matter The RV217 cohort of acutely infected individuals recruited within days of infection in Uganda, Tanzania, Kenya and Thailand. Their close monitoring with testing twice a week before infection and repetitive visits after infection allowed the precise definition of the kinetics of viral replication. In that cohort, the peak viral load was reached 13 days after first RNA positive test. The immunological events in these first few days are crucial for disease progression but have not been extensively studied because of the difficulty to collect sample in this short window of time. Most immunological stidues have well characterize the response after peak and shown that they are dysfunctional. Robb et al., NEJM 2016
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Window of Opportunity in AHI
Dysfunctional cellular immune responses I II III SEARCH010/RV254 cohort This is illustrated in this graph where after peak viral load, immune responses are dysfunctional but a window of opportunity might exist early in AHI where the immune system is still functional and initiation of ART at this early stage might preserve it. The RV254 cohort of participants recruited within days of HIV infection are enrolled and initiate ART immediately. In this cohort, participants identified and treated in the first 3 stages of AHI prior to peak and at peak viremia and enrolled. Blood but also tissues including lymph nodes are sampled to analyze the quality of the immune responses in these first few days. McMichael Nat Rev Immunol 2010; Ananworanich, J Virus Erad 2016
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Early ART Limits HIV Reservoir Size
Nicolas Chomont and Louise Leyre measured the HIV DNA content in these different groups of HIV infected individuals initiating ART at Fiebig I, II, III, IV and compared to individuals treated during chronic infection. Prior to treatment, HIV DNA levels were similar between the different groups except for the Fiebig I, but after ART initiation, all the participants treated in AHI had lower levels of HIV DNA than the participants treated in the chronic phase with the Fiebig I being almost all undetectable on treatment. Leyre, Chomont
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IS EARLY ART IN AHI PRESERVING IMMUNE FUNCTIONS AND IMPACTING THE HIV RESERVOIR?
In that cohort, we asked whether early ART in the different Fiebig stages could preserve immune function and impact the size of the HIV reservoir.
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Early ART Preserves the Resting Memory B Cell Compartment
Elias Haddad and Roshell Muir analyzsed the B cell compartment and showned a loss of resting memory B cells in acute HIV infection at Fiebig III but these numbers were restored after 72 weeks of ART to levels simiar to uninfected individuals in contrast to chronically treated donors Muir et al., Plos Pathogens 2016
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Circulating CD4 T-follicular Helper Cells Lose Function during AHI
Loss of CD4 T-follicular helper cell function in acute HIV infection resulting in lower secretion of total and HIV-specific IgG after Tfh/B cell coculture Muir et al., Plos Pathogens 2016
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Lack of CD4 T-follicular Helper Cells in Lymph Nodes in AHI
CXCR5 PD-1 Frequencies of CD4 Tfh cells in LN remain low in AHI except for a transient increase at stage 2 and are associated with frequencies of germinal center B cells Buranapraditkun
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Delayed Differentiation of Effector CD8 T Cells in AHI
Takata, Sci Transl Med, 2017
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Delayed Effector CD8 T Cell Responses in Lymph Nodes in AHI
Bcl-2 Ki-67 CD8 T cells showed similar frequencies of proliferating effector cells starting in AHI stage 2 and increasing over the course of AHI in blood and LN Buranapraditkun
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Effector CD8 T Cells Impact Viral Load Decrease After ART Initiation in AHI
START Stage 1 Stage 2 Stage 3 Takata, Sci Transl Med, 2017
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Effector CD8 T Cells Become Short-Lived and Lose Function during AHI
Stage 1 Stage 2 Stage 3 IFN-g+TNF-a+IL-2+ cells (%) Takata, Sci Transl Med, 2017
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Effector CD8 T Cells Persisting After ART Initiation in AHI Impact HIV Reservoir
Week 36 ART START Takata, Sci Transl Med, 2017
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Early ART in AHI Preserves Memory HIV-specific CD8 T Cells
CD45RA- 0.01 100 5.5yrs on ART started in AHI stage 1 100 A11 Nef CCR7 CD127 CD8 CD27 Perforin TTM TCM Perforin IL-7R Influenza Memory CD8 T cells HIV Memory CD8 T cells ART in AHI HIV Memory CD8 T cells ART in CHI
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Conclusions Very early ART limits HIV reservoir seeding by:
limiting viral load burden prior to peak VL preserving potent effector CD8 T cells at peak VL Very early ART in AHI results in: preserving the resting memory B cell compartment preventing impairment of cTfh-dependent humoral responses maintaining HIV-specific CD8 T cells with higher memory potential
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Very Early ART for Immune-Mediated Post-Treatment Control Strategies
ART initiated in: Acute Infection Chronic Infection AHI HIV Reservoir Low High Immune Responses Preserved Memory Exhausted Memory HIV RNA Immune-based strategies to boost the preserved memory HIV immunity STOP Post-TreatmentControl ART
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Acknowledments RV254 participants Funding from U.S. MHRP,
Thai Red Cross Praphan Phanuphak Nipat Teeratakulpisarn Nittaya Phanuphak Eugene Kroon Mark de Souza Donn Colby Nitiya Chomchey Carlo Sacdalan James Fletcher Pornpen Tantivitayakul Phillip Chan Jintana Intasan Many more Chulalongkorn Kiat Ruxrungtham Sunee Sirivichayakul Rungsun Rerknimitr Sukalya Lerdlum Phandee Wattanaboonyongcharoen Ponlapat Rojnuckarin Sopark Manasnayakorn U Montréal Nicolas Chomont Remi Fromentin Louise Leyre Marta Massanella AFRIMS Robert O’ Connell Kirsten Smith Sandhya Vasan Alexandra Schuetz Siriwat Akapirak Denise Hsu Tanyaporn Wansom Rapee Trichavaroj Bessara Nantapinit COG Bamrasnaradura Suthat Chottanapund NIH Irini Sereti Daniel Douek Eli Bortiz Frank Maldarelli Leidos-NCI Frederick Jeff Lifson Jacob Estes Claire Deleage Robert Gorelick Robin Dewar UCSF Victor Valcour Joanna Hellmuth Jennifer Daniels Yale Serena Spudich Leah Le UNC Gail Henderson RTI International Holly Peay U Minnesota Timothy Schacker UTMB Netanya Sandler Case Western Rafick Sekaly Drexel Elias Haddad Roshell Muir U Missouri Robert Paul U Hawaii Lishomwa Ndhlovu Napapon Sailasuta U Melbourne Sharon Lewin U PIttsburgh John Mellors Sharon Riddler RV254 participants Funding from U.S. MHRP, NIAID R01AI108433, NIMH R01MH106466
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Acknowledments U.S. MHRP Nelson Michael Merlin Robb Julie Ake
Jintanat Ananworanich Sheila Peel Sodsai Tovanabutra Linda Jagodzinski Vicky Polonis Diane Bolton Mike Eller Shelly Krebs Leigh Ann Eller Morgane Rolland Rasmi Thomas Trevor Crowell Suteeraporn Pinyakorn Ellen Turk Madelaine Ouellette Oratai Butterworth Flow Core Many more Cellular Immunology Section Hiroshi Takata Julie Mitchell Supranee Buranapraditkun Caroline Subra Julia Garnett Noemia Lima Stephen Blackmore Aaron Sy Faria Fatmi Nikiah Dawson Thai GPO ViiV Healthcare Merck Gilead
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