Date Published: July 3, 2017
Publisher: Public Library of Science
Author(s): Rafiq Nabi, Zina Moldoveanu, Qing Wei, Elizabeth T. Golub, Helen G. Durkin, Ruth M. Greenblatt, Betsy C. Herold, Marek J. Nowicki, Seble Kassaye, Michael W. Cho, Abraham Pinter, Alan L. Landay, Jiri Mestecky, Pamela A. Kozlowski, Aftab A. Ansari.
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 design of HIV vaccines and improved therapies for existing infections would benefit greatly from the identification of humoral and cellular immune responses that prevent or control human immunodeficiency virus type 1 (HIV) infection. Toward this goal, the innate and adaptive immune responses in blood of HIV-infected elite controllers (EC) have been intensively investigated in the last decade. Many EC maintain CD4 T cells in a normal range and naturally suppress HIV replication to levels that are undetectable using conventional PCR . Numerous immunological differences have been noted between EC and HIV-infected progressors [1, 2]. However, most of these could be attributed to the severe immune system dysfunction in the progressors as a result of prolonged high viremia and CD4 T cell loss. Therefore, it may be more informative to search for immunological differences between EC and chronically-infected individuals who also have undetectable viremia and similar numbers of CD4 T cells as a result of HAART.
Comparative analyses of immune responses in EC to those in infected aviremic subjects who can only control HIV infection with HAART may provide clues as to the types of immune responses that should be generated by HIV vaccines to achieve optimal control of infection. In this study, we found that EC had HIV-specific serum IgA responses that differed from those in HC in several respects. The IgA in EC recognized more HIV proteins, especially gp160 Env and p55 and p24 Gag proteins. The EC also had higher-avidity IgA antibodies to gp41 and higher magnitude IgA responses to the gp41 HR1 region, a target of gp41/intestinal microbiota cross-reactive IgG antibodies described in normal and HIV-infected individuals [23, 48]. However, we could find no evidence that these cross-reactive antibodies were present in EC or other study subjects.