Independent evolution of Fc‐ and Fab‐mediated HIV‐1‐specific antiviral antibody activity following acute infection

Abstract

Fc-related antibody activities, such as antibody-dependent cellular cytotoxicity (ADCC), or more broadly, antibody-mediated cellular viral inhibition (ADCVI), play a role in curbing early SIV viral replication, are enriched in human long-term infected non-progressors, and could potentially contribute to protection from infection. However, little is known about the mechanism by which such humoral immune responses are naturally induced following infection. Here we focused on the early evolution of the functional antibody response, largely driven by the Fc portion of the antibody, in the context of the evolving binding and neutralizing antibody response, which is driven mainly by the antibody binding fragment (Fab). We show that ADCVI/ADCC-inducing responses in humans are rapidly generated following acute HIV-1 infection, peak at approximately 6 months post-infection, but decay rapidly in the setting of persistent immune activation, as Fab-related activities persistently increase. Moreover, the loss of Fc activity occurred in synchrony with a loss of HIV-specific IgG3 responses. Our data strongly suggest that Fc- and Fab-related antibody functions are modulated in a distinct manner following acute HIV infection. Vaccination strategies intended to optimally induce both sets of antiviral antibody activities may, therefore, require a fine-tuning of the inflammatory response.

Fc functional antibodies in humans with severe H7N9 and seasonal influenza

“…Nonetheless, our work represents the largest analysis of Fc functional Abs in clinically relevant influenza to date, and a large time gap between Fc functional Abs and NAbs was observed across two independent cohorts. Similar patterns of more rapid generation of Fc functional Abs than NAbs have been reported in other infectious diseases, such as HIV (46).…”

Contrasting Adult and Infant Immune Responses to HIV Infection and Vaccination

“…The development of ADCC activity in older HIV-infected infants is comparable to that in adults in whom ADCC responses can be detected within the first months of infection (49). Interestingly, whereas in adults, the ADCC response peaks around 4 months postinfection and decreases thereafter (49), in some infants, ADCC antibody levels continue to increase for more than a year after infection (46). Importantly, until now, investigations of ADCC responses have only been conducted on a restricted number of infected infants.…”

“…Interestingly, while a delay in the development of ADCC-mediating responses is also observed in infants infected during the first 6 weeks of life, ADCC antibodies can be detected as early as 2 months postinfection when infants are infected later in life (46). The development of ADCC activity in older HIV-infected infants is comparable to that in adults in whom ADCC responses can be detected within the first months of infection (49). Interestingly, whereas in adults, the ADCC response peaks around 4 months postinfection and decreases thereafter (49), in some infants, ADCC antibody levels continue to increase for more than a year after infection (46).…”

Comparison of Antibody-Dependent Cell-Mediated Cytotoxicity and Virus Neutralization by HIV-1 Env-Specific Monoclonal Antibodies

“…ADCC responses are detectable in plasma shortly after the resolution of acute viremia and correlate inversely with disease progression (14)(15)(16)(17)(18)(19)(20). Greater ADCC responses have also been observed in individuals who exhibit elite control of HIV-1 in the absence of antiretroviral therapy (21,22).…”