Differences in serum IgA responses to HIV-1 gp41 in elite controllers compared to viral suppressors on highly active antiretroviral therapy

Abstract

Mechanisms responsible for natural control of human immunodeficiency type 1 (HIV) replication in elite controllers (EC) remain incompletely defined. To determine if EC generate high quality HIV-specific IgA responses, we used Western blotting to compare the specificities and frequencies of IgA to HIV antigens in serum of gender-, age- and race-matched EC and aviremic controllers (HC) and viremic noncontrollers (HN) on highly active antiretroviral therapy (HAART). Concentrations and avidity of IgA to HIV antigens were measured using ELISA or multiplex assays. Measurements for IgG were performed in parallel. EC were found to have stronger p24- and V1V2-specific IgG responses than HN, but there were no IgG differences for EC and HC. In contrast, IgA in EC serum bound more frequently to gp160 and gag proteins than IgA in HC or HN. The avidity of anti-gp41 IgA was also greater in EC, and these subjects had stronger IgA responses to the gp41 heptad repeat region 1 (HR1), a reported target of anti-bacterial RNA polymerase antibodies that cross react with gp41. However, EC did not demonstrate greater IgA responses to E. coli RNA polymerase or to peptides containing the shared LRAI sequence, suggesting that most of their HR1-specific IgA antibodies were not induced by intestinal microbiota. In both EC and HAART recipients, the concentrations of HIV-specific IgG were greater than HIV-specific IgA, but their avidities were comparable, implying that they could compete for antigen. Exceptions were C1 peptides and V1V2 loops. IgG and IgA responses to these antigens were discordant, with IgG reacting to V1V2, and IgA reacting to C1, especially in EC. Interestingly, EC with IgG hypergammaglobulinemia had greater HIV-specific IgA and IgG responses than EC with normal total IgG levels. Heterogeneity in EC antibody responses may therefore be due to a more focused HIV-specific B cell response in some of these individuals. Overall, these data suggest that development of HIV-specific IgA responses and affinity maturation of anti-gp41 IgA antibodies occurs to a greater extent in EC than in subjects on HAART. Future studies will be required to determine if IgA antibodies in EC may contribute in control of viral replication.

The Multifaceted Nature of Immunoglobulin A and Its Complex Role in HIV

“…119 Furthermore, ECs have been shown to demonstrate a wider breath of HIV protein recognition and higher avidity serum IgA antibodies to gp41. 73 Surprisingly, ECs have been found to have stronger Env C1-specific IgA responses compared with noncontrollers in this recent study, which opposes the finding that IgA-C1 responses in RV144 vaccines are associated with risk. The authors go on to suggest that the specificities of anti-gp120…”

“…71 HIV also preferentially infects activated HIV-infected CD4 + T cells, 72 thus it has been hypothesized that this may contribute to the decrease in CD4 + T cell help and class switching of anti-HIV IgA, while having less of an effect upon humoral responses to other infectious diseases. 51,73 As HIV also preferentially infects activated CD4 + T cells, dysfunctional class switch recombination may be targeted to specific activated antigen-specific T cells. The precise mechanisms behind why this skewed IgA/IgM isotype ratio occurs in HIV infection for certain microbial antigens, but not others, warrant further investigation.…”

“…114 Serum Anti-HIV IgA: Evidence for a Protective Role Despite the studies discussed above, which cast a cloud over the protective effect of serum IgAs in HIV, a number of potentially protective qualities, such as ADCC, 115 neutralization, 116 and phagocytosis, 117,118 have been attributed to serum anti-HIV IgA. 73,117 In one such recent study, two HIV envelope IgA mAbs were isolated and characterized from peripheral blood memory B cells from an RV144-vaccinated individual and were found to induce viral phagocytosis and block gp140 binding to the alternative HIV receptor galactosylceramide. 117 In another recent study, targeting of HIV with envelope-specific gp41 IgA mAbs engaged CD89 on HIV-infected monocytes to trigger cell lysis by ADCC.…”

Serum IgA Fc effector functions in infectious disease and cancer

“…The protective potential of serum IgA has been suggested in elite controllers (individuals that spontaneously control HIV‐1 viremia) in whom higher titers of HIV‐1‐specific serum IgA have been observed compared with HIV‐1 progressors . In vitro studies have demonstrated that monoclonal IgA has the capacity to activate antibody functions against HIV‐1 antigens (ADCC and phagocytosis) .…”

Vaccine induction of antibodies and tissue-resident CD8+ T cells enhances protection against mucosal SHIV-infection in young macaques

“…The avidity of serum IgG Abs to gp140 C.1086 or gp120 1157ipd3N4 protein was measured using NaSCN displacement ELISA as described (67). The avidity index was calculated by dividing the concentration of antibodies in wells treated with 1.5 M NaSCN for 10 minutes at 37°C by the concentration of antibodies in untreated wells.…”