Dysregulation of IgA responses in HIV-1-infected individuals

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DESCRIPTION (provided by applicant): Worldwide, the majority of HIV-1 infections is transmitted across the mucosal surfaces of the genital and intestinal tracts. Importantly, the earliest and most dramatic immunologic alterations occur in the intestinal mucosa and opportunistic infections of mucosal surfaces cause substantial morbidity in untreated patients. Thus, HIV-1 infection may be viewed as primarily a mucosal disease. A central component of mucosal defense mechanisms is IgA, the major immunoglobulin isotype responsible for the defense against mucosal pathogens and regulation of immune responses to common microbiota and environmental antigens. Since CD4+ T cells play a critical role in the regulation of class switching, somatic hypermutation, and transepithelial transport of IgA, their profound depletion from mucosal tissues, particularly intestinal mucosa, is likely to result in severe perturbations in antigen-specific IgA production and secretion. Although deficiencies in IgG responses to various pathogens have been well documented in HIV-1-infected patients, IgA responses have not been critically investigated. We and others have recently obtained data suggesting a severe impairment of antigen-specific IgA responses in HIV-1-infected individuals. Understanding the mechanisms underlying this deficiency is paramount to the understanding of HIV-1 pathogenesis and the design of vaccines against HIV-1 and other mucosal pathogens. We hypothesize that: (1) HIV-1 infection is associated with a profound suppression of IgA responses and the level of IgA unresponsiveness is proportional to the level of depletion of CD4+ T cells at mucosal tissues and polyclonal activation of IgA-producing B cells; and (2) Inability to mount specific IgA responses results in an impairment of the mucosal barrier and increased absorption of environmental antigens to the systemic compartment contributing to the chronic activation of T cells characteristic for HIV-1 infection. These hypotheses will be tested in three Specific Aims: 1) Determine whether HIV-1 infection dysregulates mucosal and systemic IgA responses to common microbial and food antigens; 2) Determine whether HIV-1 infection causes an impairment of lgA1 and lgA2 responses following mucosal and systemic immunization with previously encountered antigens; and 3) Determine whether HIV-1 infection abrogates IgA response to newly encountered antigens. In addition, we will evaluate the correlations between the responsiveness to immunization and the levels of CD4+T cell depletion in blood and intestinal mucosa, viral load, ratio of naive versus memory B cells, systemic activation of T cells, plasma levels of bacterial lipopolysaccharide, and other clinical and immunological parameters.