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.
Highlights
HIV-1 viremic controller (VC) patients represent a unique population of individuals who naturally suppress HIV replication in the absence of highly active antiretroviral therapy (HAART) [1, 2]
To exploit the potential of tetherin to increase the detection of cell-surface viral antigens, we developed an HIV-infected, cell-based system that allows for the characterization of Abs that bind cell-associated and virus incorporated (CANVI) forms of HIV Env
We examined the level of patient Ab binding to HIV-1 Envs using IgG purified from the plasma of 18 HIV+ VC patients, 27 HIV+ chronically infected patients (CIP) on HAART, and 5 HIV– donors (Table 1)
Summary
HIV-1 viremic controller (VC) patients represent a unique population of individuals who naturally suppress HIV replication in the absence of highly active antiretroviral therapy (HAART) [1, 2]. These VC patients can be divided into 2 subgroups made up of long-term nonprogressors (LTNPs) and elite controllers (ECs). In the RV144 HIV vaccine trial, a small reduction in HIV acquisition correlated with the induction of nonneutralizing IgG Ab responses that mediate ADCC after controlling for IgA responses [10, 11] Given this common feature, further characterization of IgG responses from VCs may yield valuable insights into the mechanisms that underlie potent antiviral Fc effector responses and identify Ab profiles that may be desirable to emulate in HIV vaccine strategies
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