IgG Subclass Profiles in Infected HIV Type 1 Controllers and Chronic Progressors and in Uninfected Recipients of Env Vaccines

Abstract

We have studied IgG subclass responses to the HIV-1 proteins gp120, gp41, p24, and Tat in individuals who control their infection without using antiretroviral drugs (HIV-1 controllers; HC) or who progress to disease (chronic progressors; CP). We also measured IgG subclass titers to gp120 in vaccinated individuals. In all cases, the IgG1 subclass dominated the overall response to each antigen. The only IgG titer that differed significantly between the HC and CP groups was to the p24 Gag protein, which was higher in the HC group. IgG1 titers to both p24 and gp120 were significantly higher in the HC group, and IgG3 anti-gp120 antibodies, although rare, were detected more frequently in that group than in CP. Overall, significantly more patients had IgG2 antibodies to gp120 than to gp41. Antibodies to other IgG subclasses were infrequent and their frequency or titers did not differ between the two patient groups. Anti-gp41 and anti-Tat responses also did not correlate with immune control, and anti-Tat antibodies were infrequently detected. Although we found isotypic differences in IgG responses to HIV-1 antigens among vaccinees and the HC and CP individuals, there were no indications of differential T(H)1:T(H)2 polarization between the different groups.

Natural variation in Fc glycosylation of HIV-specific antibodies impacts antiviral activity

“…No differences were observed in antibody titer or IgG subclass distribution in either bulk or HIV-specific antibodies among the different patient populations (data not shown), consistent with previous reports (21), suggesting that these features could not account for the differences observed in ADCVI activity. In contrast, enzymatic removal of the glycan from the antibody heavy chain resulted in profound loss of ADCVI activity ( Figure 1C).…”

“…Analysis was performed to verify that brief acid exposure did not alter glycan composition and that gp120 was not released from the resin. Antibodies titers were determined by ELISA as described previously (21), and enrichment of gp120-specific antibodies was confirmed by ELISA.…”

Exploring the Potential of Monoclonal Antibody Therapeutics for HIV-1 Eradication

“…127 Interestingly, reduced risk of infection was associated with the selective induction of HIVspecific IgG3 antibodies that exhibit a polyfunctional profile, able to simultaneously recruit ADCC, ADCP, and NK degranulation, potentially providing enhanced protection from diverse modes of HIV acquisition through a broader capacity to recruit a variety of innate immune effector cells. Similarly, spontaneous control of HIV infection is associated with the selective induction of gp120-specific IgG3 antibodies, 54 which normally decline following acute infection in noncontrollers. 128 These data strongly argue that IgG3 antibodies, despite their short serum half-life, represent a potent Fc modification able to rapidly control and clear HIVinfected cells.…”

“…Beyond Env-specific targeting approaches, a few studies have observed an enrichment of HIV Gag-specific 54 and other regulatory/accessory protein-specific antibodies 55 in subjects who durably control HIV infection in the absence of therapy. These antibodies against non-Env targets have been shown to mediate ADCC.…”

HIV-1 vaccines

“…77 Antigen-specific IgG3 antibodies are associated with long-term control of Plasmodium falciparum 78 and monocyte-mediated cellular inhibition of parasite growth in vitro. 79 Similarly, early appearance of chikungunya virus-specific IgG3 neutralizing antibodies is associated with clearance of the virus and long-term clinical protection.…”