Enhanced FCGR2A and FCGR3A signaling by HIV viremic controller IgG

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.

HIV Controllers Have Low Inflammation Associated with a Strong HIV-Specific Immune Response in Blood

“…Although the role of the Fc receptors in virus control remains to be thoroughly explored, one can speculate that the downregulation of these receptors could be associated with both lower activation/inflammation and the HIV reservoir observed in HIC compared to cART-treated individuals (40). It was also reported that the quality rather than the quantity of FCGR signaling could be responsible for the wider polyfunctional Fcmediated responses observed in HIC (36,41). In parallel, there is a downregulation in HIC of mitogen-activated protein kinase 1 (MAPK1) and PI3-kinase (PIK3CG and PIK3CB); both are critical regulatory factors of immune stimulation and suppression during inflammation (15,16,42).…”

P2X1 Selective Antagonists Block HIV-1 Infection through Inhibition of Envelope Conformation-Dependent Fusion

“…(D) Tetherin-high antibody binding assay indicates binding of the indicated antibody in the presence of the indicated drug, NF279 (left) or NF449 (right). Binding index (BI) was calculated for each anti-HIV antibody by multiplying the percent Ab binding within the entire HIV ϩ population against the MFI ratio of HIV-positive over HIV-negative cells (56,57). Results are the means Ϯ SEMs from at two or three independent experiments.…”

“…To further explore the hypothesis that NF279 and NF449 activities are dependent on direct binding to the HIV-1 Env V1V2 region, the PG9 binding site, we employed a well-characterized antibody binding system that retains viral particles on the surface of HIV-infected CD4 ϩ T cells (55)(56)(57). This system is based on high expression of tetherin on cells, which allows for the enhanced resolution of differences in antibody binding.…”

“…Tetherin-high antibody binding assay. A cell-based assay for bNAb binding was used as previously described (56) in which a subclone of the Jurkat E6 CD4 T cell line, which constitutively expresses high levels of tetherin, was transfected with an HIV-1 NL4-3 Δvpu mCherry fluorescent reporter virus. Cells retained virus particles on their surface.…”

“…Plots depict the level of anti-HIV antibody binding (APC) to HIV ϩ cells (mCherry ϩ ) treated with DMSO control, NF449, or NF279. Binding index (BI) was calculated for each anti-HIV antibody by multiplying the percent Ab binding within the entire HIV ϩ population against the mean fluorescence intensity (MFI) ratio of HIV-positive over HIV-negative cells, as previously described (56,57).…”