CROI 2016 Abstract eBook

Abstract Listing

Oral Abstracts

91 Neutrophil Functions Induced by Gp-120 Specific IgA and IgG; Clues for Immunotherapy Magdalena Sips 1 ; Marina Krykbaeva 1 ; Anne Sophie Dugast 1 ; Fernanda Cerqueira 1 ; Peter Brouckaert 2 ; Galit Alter 1 1 Ragon Inst of MGH, MIT, and Harvard, Cambridge, MA, USA; 2 Ghent Univ, Gent, Belgium

Background: While neutropenia has been associated with increased risk of HIV infection, the antiviral role of neutrophils in HIV infection has been poorly studied. However, neutrophil extracellular traps have been shown to capture HIV virions that were subsequently eliminated by myeloperoxidase and α-defensins. Moreover, neutrophils are the most abundant cells in the blood, the most rapid responders to infection and the most potent mediators of Fc-effector functions. Thus functional antibodies against HIV may have the capacity to rapidly recruit and direct the potent antiviral activity of this cell subset. Given the high levels of both IgG-responsive FcγRs and IgA-responsive FcαR, here we aimed to determine whether HIV-specific antibodies may be functionalized naturally during HIV infection or whether monoclonal therapeutics can be designed to selectively recruit the antiviral activity of neutrophils. Methods: Serum IgA and IgG were purified from HIV-infected subjects and healthy controls. Their ability to activate different neutrophil functions, such as phagocytosis against gp120 antigen, release of elastase and mediators of oxidative stress, were assessed on peripheral blood neutrophils from healthy donors. Results: Significant differences in HIV-specific IgA titers were observed in HIV infected patients, with controllers exhibiting significantly higher gp120-specific IgA1 and IgA2 titers than progressors. Both HIV-specific IgA and IgG induced rapid phagocytosis (as early as 40 minutes post-stimulation) with the same potency, however IgGs were significantly better at promoting continual phagocytosis over 24 hours. IgA, on the other hand, were more potent in inducing neutrophil degranulation. Gp120 specific IgA2 and IgG1 titers correlated positively with phagocytosis, however only IgA2 strongly correlated with neutrophil degranulation. Additionally, antibody glycosylation profiles were linked to neutrophil activity, highlighting antibody biophysical features that drive enhanced neutrophil mediated activity. Conclusions: HIV infection, and specifically durable control of HIV in Controllers, is associated with the production of antibodies with the selective capacity to rapidly recruit and deploy the antiviral activity of neutrophils through the production of both IgG and IgA antibodies. These data highlight a novel means by which vaccine strategies or monoclonal immunotherapies may be designed to harness tremendous anti-viral potential of neutrophils in the context of prophylaxis or cure strategies. 92 Potency and Kinetics of Autologous HIV-1 Neutralizing Antibody Responses During ATI Brenda Salantes ; Benjamin Scheinfeld; Katharine J. Bar Univ of Pennsylvania, Philadelphia, PA, USA Background: Studies utilizing brief analytical treatment interruption (ATI) of cART in HIV-1 infected subject have consistently shown that viral rebound occurs rapidly upon treatment interruption. The viral dynamics and relevant host immune pressures at this juncture, however, remain unclear. To test the hypothesis that the autologous antibody response is a significant driver of virus selection during ATI, we identify the viral populations arising from latency and measure the potency and kinetics of the autologous antibody response. Methods: Plasma samples from 11 chronically infected, cART-suppressed subjects undergoing ATI were studied by single genome sequencing (SGS) and maximum likelihood analysis of gp160 env . Consensus env s from each lineage were cloned and tested for neutralization sensitivity in TZM-bl assays. Results: We generated 231 SGS-derived envs (range: 16-29/subject timepoint). Multiple low-diversity lineages (2 to >10/subject) comprised the rebound quasispecies at first detectable viremia. Envs representing initial rebound lineages displayed a range of neutralization sensitivities to autologous plasmas (IC 50 <1:50 to >1:5,000). In three subjects studied over 12 weeks of ATI, neutralization resistant viruses persisted while more sensitive lineages substantially decreased in frequency. For example, subject S05 rebounded with four genetically distinct lineages (total env diversity of 1.48%; within-lineage diversity of <0.17%); each lineage was moderately sensitive to week 4 plasma (IC 50 range: 1:240-1:420). Over time, titers to the largest lineage (8/20 sequences at week 4) rose to >1:3000 and this lineage was not sampled subsequently (0/18 sequences, week 10). Minor lineages, in contrast, became more resistant to longitudinal plasmas (IC 50 ~1:100 to week 10 plasma) and expanded to comprise the majority of the viral quasispecies (15/18 sequences, week 10). Conclusions: This study demonstrates that HIV-infected individuals undergoing ATI have multiple genetically distinct rebounding viral lineages exhibiting a range of sensitivities to autologous antibodies. Results suggest that the autologous neutralizing antibody response during ATI exerts potent selective pressure and is a significant factor determining viral quasispecies composition. These findings contribute to our understanding of relevant immune pressures during ATI and suggest that autologous antibodies may contribute to virus suppression achieved with novel immunotherapies currently being tested in the context of ATI.

Oral Abstracts

35

CROI 2016