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Enhanced FCGR2A and FCGR3A signaling by HIV viremic controller IgG
Raymond A. Alvarez, … , Viviana Simon, Benjamin K. Chen
Raymond A. Alvarez, … , Viviana Simon, Benjamin K. Chen
Published February 23, 2017
Citation Information: JCI Insight. 2017;2(4):e88226. https://doi.org/10.1172/jci.insight.88226.
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Research Article AIDS/HIV Infectious disease

Enhanced FCGR2A and FCGR3A signaling by HIV viremic controller IgG

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Abstract

HIV-1 viremic controllers (VC) spontaneously control infection without antiretroviral treatment. Several studies indicate that IgG Abs from VCs induce enhanced responses from immune effector cells. Since signaling through Fc-γ receptors (FCGRs) modulate these Ab-driven responses, here we examine if enhanced FCGR activation is a common feature of IgG from VCs. Using an infected cell–based system, we observed that VC IgG stimulated greater FCGR2A and FCGR3A activation as compared with noncontrollers, independent of the magnitude of HIV-specific Ab binding or virus neutralization activities. Multivariate regression analysis showed that enhanced FCGR signaling was a significant predictor of VC status as compared with chronically infected patients (CIP) on highly active antiretroviral therapy (HAART). Unsupervised hierarchical clustering of patient IgG functions primarily grouped VC IgG profiles by enhanced FCGR2A, FCGR3A, or dual signaling activity. Our findings demonstrate that enhanced FCGR signaling is a common and significant predictive feature of VC IgG, with VCs displaying a distinct spectrum of FCGR activation profiles. Thus, profiling FCGR activation may provide a useful method for screening and distinguishing protective anti-HIV IgG responses in HIV-infected patients and in monitoring HIV vaccination regimens.

Authors

Raymond A. Alvarez, Ana M. Maestre, Kenneth Law, Natasha D. Durham, Maria Ines Barria, Akiko Ishii-Watabe, Minoru Tada, Manav Kapoor, Mathew T. Hotta, Gabriela Rodriguez-Caprio, Daniel S. Fierer, Ana Fernandez-Sesma, Viviana Simon, Benjamin K. Chen

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Figure 1

Cell-based HIV-specific Ab binding system.

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Cell-based HIV-specific Ab binding system.
(A) Diagram depicts HIV-1 pNL...
(A) Diagram depicts HIV-1 pNL4.3 construct with mCherry expressed in place of HIV Nef with Nef expression restored by an internal ribosome entry site (IRES), Δvpu mutation disrupts the vpu initiation codon. (B) Diagram of HIV Ab binding to tetherinhigh CD4+ Jurkat cells infected with an HIV-1 Δvpu Cherry–expressing reporter virus. (C) Graph illustrates the reproducibility of epitope detection across 3 separate binding assay replicates using 4 broadly neutralizing monoclonal antibodies (b12; PG9; 830A; 2F5) and non-neutralizing Ab A32, recognizing distinct regions and epitopes within HIV envelope. IgG from an HIV– donor was used as a negative control for binding assay background.

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