CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

254 TARGETING TYPE I INTERFERON-MEDIATED IMMUNE ACTIVATION TO CONTROL HIV INFECTION Anjie Zhen 1 , Mayra A. Carrillo 1 , Valerie Rezek 1 , David Brooks 2 , Scott G. Kitchen 1 1 Univ of California Los Angeles, Los Angeles, CA, USA, 2 Princess Margaret Cancer Cntr, Toronto, Ontario, Canada

Background: Chronic immune activation is a hallmark of HIV infection, simultaneously contributing to and combating viral replication. Persistent antigen stimulation during HIV infection leads to immune exhaustion and dysfunction, which has negative effects in the body’s ability to suppress the virus. How immune dysfunction develops during chronic viral infection is largely unknown and the systematic and longitudinal characterization of immune activation and the mechanisms driving these processes are lacking. We are seeking to define the mechanisms driving immune dysfunction during HIV infection. Methods: In this study we closely examined the development of immune dysfunction during HIV infection in vivo utilizing the NSG-BLT humanized mouse model. As chronic activation can be a driving force in immune dysfunction and type I interferons (IFN-I) are emerging as critical components underlying ongoing activation in HIV infection, we tested the effect of blocking IFN-I signaling during chronic HIV infection through therapeutic antibody blockade of the IFN-I receptor (IFNR) with and without antiretroviral therapy (ART). Results: We found that, similar to that seen in HIV-infected individuals, chronic HIV infection of humanized mice led to significantly increased expression of immune activation molecules, including IFN-I response genes, and T cell exhaustion molecules over time. We determined that T cells from HIV-1 infected mice become functionally defective and have the impaired ability to secrete cytokines and kill infected cells. We demonstrate that blockade of IFN-I signaling during chronic HIV infection in vivo diminished HIV-driven immune activation, decreased T cell exhaustion molecule expression, restored HIV-specific CD8 T cell functions, and led to decreased viral replication. ART in combination with IFN-I blockade further decreased viral loads and reduced the latent HIV reservoir compared to ART treatment alone. Conclusion: Our data suggest that chronic expression of IFN-I, in addition to persistent antigen stimulation, contributes to the development of dysfunctional T cells during HIV infection. We found that characteristics of immune activation and dysfunction in HIV infected humanized mice closely recapitulates that found in humans. This sets the stage for the closer examination of the mechanisms behind these defects in T cell responses to further suppress or eradicate HIV infection and the use of IFNR blockade as a therapeutic strategy to enhance antiviral immune responses. 255 METFORMIN REDUCES T-CELL EXHAUSTION IN A CLINICAL TRIAL OF HIV-INFECTED ADULTS ON ART Glen Chew 1 , Dominic Chow 1 , Scott A. Souza 1 , Lindsay Kohorn 1 , Richard M. Watanabe 2 , Ivo Sah Bandar 1 , Eun-Young Park 1 , Mary Margaret Byron 1 , Lishomwa C. Ndhlovu 1 , Cecilia Shikuma 1 1 Univ of Hawaii, Honolulu, HI, USA, 2 Univ of Southern California, Los Angeles, CA, USA Background: Chronic HIV infection is associated with persistent inflammation and increased expression of negative checkpoint receptors (NCRs; eg: PD-1, TIM-3, TIGIT) on T cells that result in immune dysfunction (Chew et al 2016 PLoS Pathog) and viral persistence (Fromentin et al 2016 PLoS Pathog). Current scientific literature suggests that Metformin, an oral hypoglycemic agent used for diabetes, may have additional, previously unrecognized therapeutic effects against age-related conditions including anti-inflammatory properties. We assessed NCR in banked blood specimens from a small clinical trial of Metformin conducted in individuals with chronic HIV. Methods: An open label, 24 week pilot study in 12 individuals on antiretroviral therapy (ART) stable for >1year with plasma HIV RNA < 50 copies/ml, median age of 58 years and majority male (11/12) randomized 1:1 to Metformin (500 mg increasing to 1000 mg at week 4) vs Observation (OBS). We assessed surface expression of T cell exhaustion receptors (PD-1,TIM-3, TIGIT) and activation (CD38+HLA-DR+) by flow cytometry on cryopreserved peripheral blood mononuclear cells collected at enrollment and study end. Statistical analyses include nonparametric Mann-Whitney Statistical T tests. Results: Compared to OBS, Metformin led to significant 24 week decrease changes of single expressing PD-1+ CD4 T cells [Metformin -1.6 (-4.7,0.2), OBS 2.0 (0.4,3.7) p=0.026]; in dual expressing PD-1+TIGIT+ CD4 T cells [Metformin -0.9 (-2.9,-0.1), OBS 0.8 (0.2,1.2) p=0.002], and in triple expressing PD-1+TIM-3+TIGIT+ CD4 T cells [Metformin -0.9 (-1.3, -0.1), OBS (0.3 (0.07,0.6) p=0.041]. No difference in 24 week changes between the Metformin and OBS arms were observed in CD8 T cell exhaustion and CD4 or CD8 T cell activation. Conclusion: A 24 week course of Metformin reduced CD4 T cell expression of multiple NCR among virally suppressed HIV infected adults. The data suggests the unexpected benefit of Metformin in potentially improving anti-viral T cell function or impacting the persistence of CD4 T cell viral reservoirs. Metformin may have value as an adjunctive therapy to ART in chronic HIV infection.

Poster and Themed Discussion Abstracts

256 P2X PURINERGIC RECEPTORS AS THERAPEUTIC TARGETS OF HIV-1 INFECTION AND INFLAMMATION Talia Swartz 1 , Natasha Durham 2 , Alexandra Soare 1 , Meagan O’Brien 1 , Nina Bhardwaj 1 , Benjamin K. Chen 1 1 Icahn Sch of Med at Mt Sinai, New York, NY, USA, 2 Tufts Univ, Boston, MA, USA

Background: HIV-1 causes an incurable infection. Despite antiretroviral therapy, chronic inflammation persists which is associated with multiple co-morbidities. A clear mechanism for this inflammation has yet to be determined. Some of this inflammation is thought to be driven by enhanced mucosal translocation, resulting in elevated levels

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