Abstract
Anti-HIV envelope (Env) antibodies elicit important Fc receptor functions, including FcγRIIIa-mediated natural killer cell killing of opsonized infected targets. How these antibodies evolve during HIV infection and treatment remains poorly understood. We describe changes in anti-HIV Env IgG using longitudinal samples from seroconverter subjects treated soon after infection and later during periods of structured treatment interruption (STI). Our well-validated dimeric rsFcγR binding assays combine effects of opsonizing antibody subclasses, epitopes, and geometries to provide a measure of FcγR (Fcγ receptor)-mediated functionality. IgG1 anti-Env titers diminished rapidly during antiretroviral therapy (ART; t1/2 3.0 ± 0.8 months), while the dimeric rsFcγRIIIa activity persisted longer (t1/2 33 ± 11 months), suggesting that there is maintenance of functional antibody specificities within the diminished pool of anti-HIV Env Abs. The initial antibody response to infection in two subjects was characterized by approximately fivefold higher FcγRIIIa compared with FcγRIIa binding activity. Uncoupling of FcγRIIa and FcγRIIIa activities may be a distinct feature of the early antibody response that preferentially engages FcγRIIIa-mediated effector functions. Two to three STI cycles, even with low viremia, were sufficient to boost dimeric FcγR activity in these seroconverter subjects. We hypothesize that increased humoral immunity induced by STI is a desirable functional outcome potentially achievable by therapeutic immunization during ART. We conclude that controlled viral antigen exposure under the protection of suppressive ART may be effective in eliciting FcγR-dependent function in support of viral reactivation and kill strategies.
Highlights
This study of subjects treated with antiretroviral therapy (ART) early after infection was designed to determine if short periods of viral antigen exposure experienced during structured treatment interruption (STI) could boost functional immune responses associated with viral containment, which are otherwise suppressed during continuous ART
With the aid of very frequent patient blood sampling during these STI cycles, we demonstrated boosting of both IgG responses, dimeric rsFccR binding activity and T cell immunity, which contributed to virological control in some individuals
The study confirmed that rapid decline in anti-envelope Ab titer occurs early during suppressive ART, but boosting of anti-Env Abs and Fcc receptors (FccRs) binding activities was achieved after only a few STI cycles, even when viral rebound was low (e.g., 460 copies/mL)
Summary
Leukocyte activation through IgG binding to Fcc receptors (FccRs) is key to IgG-induced protective inflammatory responses, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular viral inhibition, and antigen presentation.[1,2,3,4] FccR-mediated functions augment protective antibody responses to HIV infection in macaques, mice, and humans.[5,6] A component of protection and viremic control in macaque vaccination and challenge studies is contributed by Fc-dependent functions, such as ADCC and ADCP.[7,8,9,10,11] In addition to neutralizing activity, BnAbs clear infected cells mediated through FccR binding[12] and stimulation of the endogenous antibody response.[13,14] highly protective BnAbs are rarely found in long-term a Hugh Billings et al 2019; Published by Mary Ann Liebert, Inc. Leukocyte activation through IgG binding to Fcc receptors (FccRs) is key to IgG-induced protective inflammatory responses, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular viral inhibition, and antigen presentation.[1,2,3,4] FccR-mediated functions augment protective antibody responses to HIV infection in macaques, mice, and humans.[5,6] A component of protection and viremic control in macaque vaccination and challenge studies is contributed by Fc-dependent functions, such as ADCC and ADCP.[7,8,9,10,11] In addition to neutralizing activity, BnAbs clear infected cells mediated through FccR binding[12] and stimulation of the endogenous antibody response.[13,14] highly protective BnAbs are rarely found in long-term a Hugh Billings et al 2019; Published by Mary Ann Liebert, Inc
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
