Evolution of Antibodies to Native Trimeric Envelope and Their Fc-Dependent Functions in Untreated and Treated Primary...

People living with HIV (PLWH) develop both anti-envelope-specific antibodies, which bind the closed trimeric HIV envelope present on infected cells, and anti-gp120-specific antibodies, which bind gp120 monomers shed by infected cells and taken up by CD4 on uninfected bystander cells. Both antibodies have an Fc portion that binds to Fc receptors on several types of innate immune cells and stimulates them to develop antiviral functions. Among these Fc-dependent functions (FcDFs) are antibody-dependent (AD) cellular cytotoxicity (ADCC), AD cellular trogocytosis (ADCT), and AD phagocytosis (ADCP). In this study, we assessed the evolution of total immunoglobulin G (IgG), anti-gp120, and anti-envelope IgG antibodies and their FcDFs in plasma samples from antiretroviral therapy (ART)-naive subjects during early HIV infection (28 to 194 days postinfection [DPI]). We found that both the concentrations and FcDFs of anti-gp120 and anti-envelope antibodies increased with time in ART-naive PLWH. Although generated concurrently, anti-gp120-specific antibodies were 20.7-fold more abundant than anti-envelope-specific antibodies, both specificities being strongly correlated with each other and FcDFs. Among the FcDFs, only ADCP activity was inversely correlated with concurrent viral load. PLWH who started ART at >90 DPI showed higher anti-envelope-specific antibody levels and ADCT and ADCP activities than those starting ART at<90 DPI. However, in longitudinally collected samples, ART initiation at >90 DPI was accompanied by a faster decline in anti-envelope-specific antibody levels, which did not translate to a faster decline in FcDFs than for those starting ART at <90 DPI. IMPORTANCE Closed-conformation envelope is expressed on the surface of HIV-infected cells. Antibodies targeting this conformation and that support FcDFs have the potential to control HIV. This study tracked the timing of the appearance and evolution of antibodies to closed-conformation envelope, whose concentration increased over the first 6 months of infection. Antiretroviral therapy (ART) initiation blunts further increases in the concentration of these antibodies and their and FcDFs. However, antibodies to open-conformation envelope also increased with DPI until ART initiation. These antibodies target uninfected bystander cells, which may contribute to loss of uninfected CD4 cells and pathogenicity. This report presents, for the first time, the evolution of antibodies to closed-conformation envelope and their fate on ART. This information may be useful in making decisions on the timing of ART initiation in early HIV infection.