Viremic HIV Controllers Exhibit High Plasmacytoid Dendritic Cell-Reactive Opsonophagocytic IgG Antibody Responses against HIV-1 p24 Associated with Greater Antibody Isotype Diversification.

Identifying the mechanisms of natural control of HIV-1 infection could lead to novel approaches to prevent or cure HIV infection. Several studies have associated natural control of HIV-1 infection with IgG Abs against HIV-1 Gag proteins (e.g., p24) and/or production of IgG2 Abs against HIV-1 proteins. These Abs likely exert their effect by activating antiviral effector cell responses rather than virus neutralization. We hypothesized that an opsonophagocytic IgG Ab response against HIV-1 p24 that activates plasmacytoid dendritic cells (pDCs) through FcγRIIa would be associated with control of HIV and that this would be enhanced by Ab isotype diversification. Using the Gen2.2 pDC cell line, we demonstrated that pDC-reactive opsonophagocytic IgG Ab responses against HIV-1 p24 were higher in HIV controllers (HIV RNA < 2000 copies/ml) than noncontrollers (HIV RNA > 10,000 copies/ml), particularly in controllers with low but detectable viremia (HIV RNA 75-2000 copies/ml). Opsonophagocytic Ab responses correlated with plasma levels of IgG1 and IgG2 anti-HIV-1 p24 and, notably, correlated inversely with plasma HIV RNA levels in viremic HIV patients. Phagocytosis of these Abs was mediated via FcγRIIa. Isotype diversification (toward IgG2) was greatest in HIV controllers, and depletion of IgG2 from Ig preparations indicated that IgG2 Abs to HIV-1 p24 do not enhance phagocytosis, suggesting that they enhance other aspects of Ab function, such as Ag opsonization. Our findings emulate those for pDC-reactive opsonophagocytic Ab responses against coxsackie, picorna, and influenza viruses and demonstrate a previously undefined immune correlate of HIV-1 control that may be relevant to HIV vaccine development.

Control of early HIV-1 infection associates with plasmacytoid dendritic cell-reactive opsonophagocytic IgG antibodies to HIV-1 p24.

OBJECTIVES: We have previously demonstrated that HIV-1 p24-specific plasmacytoid dendritic cell-reactive opsonophagocytic antibody (PROAb) responses associate with control of chronic HIV infection. Here, we examined whether HIV-1 p24-specific PROAbs associate with control of early HIV infection and their relationship with HIV-1 p24-specific IgG subclasses. METHODS: Plasma collected at 8 and 52 weeks following primary HIV-1 infection was obtained from antiretroviral therapy-naïve patients who were classified as 'good' (plasma HIV-1 RNA < 5000 copies/ml; n = 17) or 'poor' (HIV-1 RNA > 50 000 copies/ml; n = 15) controllers at week 52. HIV-1 p24-specific PROAb responses were assayed using a plasmacytoid dendritic cell line (Gen2.2), and HIV-1 p24-specific IgG3, IgG1 and IgG2 levels were assayed by ELISA. RESULTS: HIV-1 p24-specific PROAb responses increased in 'good controllers' (P = 0.01) but remained unchanged in 'poor controllers' between weeks 8 and 52. Of the HIV-1 p24-specific IgG subclasses measured, only IgG1 increased over this time period in 'good controllers' alone (P = 0.003), which correlated with the increase in HIV-1 p24-specific PROAb responses (r = 0.83, P < 0.0001). Depletion of IgG1 from IgG preparations of 'good controllers' resulted in the inhibition of HIV-1 p24-specific PROAb responses. In the total patient cohort, plasma HIV-1 RNA levels at week 52 correlated inversely with changes in HIV-1 p24-specific PROAb responses (r = -0.37, P = 0.04) and IgG1 (r = -0.51, P = 0.003) levels between weeks 8 and 52. CONCLUSION: Control of early HIV-1 infection was associated with an increase in HIV-1 p24-specific PROAb responses, which was mediated by HIV-1 p24-specific IgG1 antibodies. These findings provide further evidence that antibodies to HIV core proteins may contribute to control of HIV-1 infection.