Divergent Antibody Subclass and Specificity Profiles but Not Protective HLA-B Alleles Are Associated with Variable Antibody Effector Function among HIV-1 Controllers

Abstract

Understanding the coordination between humoral and cellular immune responses may be the key to developing protective vaccines, and because genetic studies of long-term HIV-1 nonprogressors have associated specific HLA-B alleles with spontaneous control of viral replication, this subject group presents an opportunity to investigate relationships between arms of the adaptive immune system. Given evidence suggesting that cellular immunity may play a role in viral suppression, we sought to determine whether and how the humoral immune response might vary among controllers. Significantly, Fc-mediated antibody effector functions have likewise been associated with durable viral control. In this study, we compared the effector function and biophysical features of HIV-specific antibodies in a cohort of controllers with and without protective HLA-B alleles in order to investigate whether there was evidence for multiple paths to HIV-1 control, or whether cellular and humoral arms of immunity might exhibit coordinated profiles. However, with the exception of IgG2 antibodies to gp41, HLA status was not associated with divergent humoral responses. This finding did not result from uniform antibody responses across subjects, as controllers could be regrouped according to strong differences in their HIV-specific antibody subclass specificity profiles. These divergent antibody profiles were further associated with significant differences in nonneutralizing antibody effector function, with levels of HIVspecific IgG1 acting as the major distinguishing factor. Thus, while HLA background among controllers was associated with minimal differences in humoral function, antibody subclass and specificity profiles were associated with divergent effector function, suggesting that these features could be used to make functional predictions. Because these nonneutralizing antibody activities have been associated with spontaneous viral control, reduced viral load, and nonprogression in infected subjects and protection in vaccinated subjects, understanding the specific features of IgGs with potentiated effector function may be critical to vaccine and therapeutic antibody development. IMPORTANCEIn this study, we investigated whether the humoral and cellular arms of adaptive immunity exhibit coordinated or compensatory activity by studying the antibody response among HIV-1 controllers with different genetic backgrounds.

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

“…Theoretically, in states in which the immune system is functional and contributing to the control of a pathogen (as in HIV controllers), a higher steady-state level of that pathogen (HIV RNA in this case) will be associated with higher host responses aimed at controlling that pathogen (IgG antibody responses) (43, 44). This proposal would provide an explanation for why other investigators have not shown an association between IgG1 or IgG2 antibodies to HIV-1 Gag proteins and control of HIV infection in unselected HIV controllers (45) or HIV controllers who did not carry ‘protective’ HLA-B alleles (46), because those studies examined predominantly, or only, elite HIV controllers.…”

Broadly Neutralizing Anti-HIV-1 Antibodies Require Fc Effector Functions for In Vivo Activity

“…Although the potential involvement of FcγR effector pathways in antibody-mediated protection against HIV-1 has been previously discussed in numerous studies (Ackerman et al, 2013; Forthal et al, 2010; Forthal et al, 2011; Lai et al, 2014; Perez et al, 2013), there is still very limited evidence on the exact contribution of Fc effector function in the protective activity of anti-HIV-1 mAbs, stemming from the lack of an in vivo model system that recapitulates FcγR functional and structural diversity. Indeed, the use of artificial in vitro systems for the study of Fc effector function poorly reflect the diversity and complexity of in vivo FcγR-mediated pathways, providing thereby limited information on the precise Fc effector mechanisms that mediate viral neutralization in vivo .…”

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

“…High levels of IgG2 antibodies targeting gp41 were reported as a strong correlate of slow progression to AIDS [172], and these antibodies are also found at high levels in HICs [173,174]. The mechanism through which these antibodies contribute to HIV control is unknown, although it seems to be unrelated to direct neutralization.…”