Streptococcus pneumoniae is the most common bacterial respiratory pathogen in human immunodeficiency virus (HIV)-infected individuals. Although vaccination with the pneumococcal polysaccharide vaccine (PPV) is recommended for all those >2 years of age infected with HIV, the response to the vaccine is less than optimal and correlates with the degree of immune suppression as measured by CD4+ T-lymphocyte count (1-10). In addition, vaccine recommendations in newly diagnosed HIV-positive persons with CD4 counts <200 and those concerning revaccination after 5 years are controversial as there is no evidence to confirm clinical or serological benefit. The poor immune response to vaccine antigens is likely related to the severe B cell dysfunction noted early in HIV disease. The viral protein, gp120, acts as a super-antigen restricted to recognition of the variable heavy chain 3 (VH3) gene segments (11). Moreover, gp120 activates proliferation and differentiation of B cells expressing the VH3 gene (11-14) resulting in progressive deletion of VH3- expressing B cells (15). Depletion of the VH3 expressing B cell population is highly significant as the VH3 gene family products encode >90% of anti-pneumococcal polysaccharide (PPS) antibodies (16-20). However, a comprehensive study, directly linking anti-PPS antibody levels, functionality and molecular structure/gene family usage has not been performed. We have modified a novel technique of single antigen-specific B cell isolation/culture allowing analysis of paired variable heavy (VH) and variable light (VL) gene usage and successfully applied this technique to PPS-specific B cells. In addition, we have recently developed a flow analysis technique that allows us to define the B cell subsets of PPS-responding B cells. This unique ability allows us to define the presence of memory B cells amongst PPS-responding B cell populations in HIV-negative, HIV-positive HAART-naive and HIV-positive HAART-treated populations. We therefore propose to perform a comprehensive study of the immune response to PPV in HIV-positive individuals.
In Specific Aim 1, we propose to define the immune response to PPV in various stages of untreated HIV infection on a quantitative, functional and molecular level, using a novel, single antigen-specific B cell isolation and culture technique.
In Specific Aim 2, we will test the hypothesis that individuals on long-term HAART therapy are capable of responding to the pneumococcal vaccine and investigate the nature of this response.
In Specific Aim 3, we will study the percentage of PPS-specific B cells that are IgM or switched memory B cells in the HIV- negative population and compare this to HIV-positive, HAART-naive and HIV-positive HAART-treated population following primary vaccination with PPV. The proposed studies are thus unique, as they will provide a comprehensive picture of the immune response to PPV in the HAART-naive and HAART-treated HIV-positive populations. More importantly, the results of these studies could clarify controversies in the present vaccine recommendations in the HIV-infected population.
The proposed studies are thus unique as they will provide a comprehensive picture of the immune response to PPV in the HAART-naive and HAART-treated HIV-positive populations. More importantly, the results of these studies could clarify controversies in the present vaccine recommendations in the HIV-infected population.
|Ohtola, Jennifer A; Khaskhely, Noor M; Saul-Mcbeth, Jessica L et al. (2016) Alterations in serotype-specific B cell responses to the 13-valent pneumococcal conjugate vaccine in aging HIV-infected adults. Vaccine 34:451-457|
|Ohtola, Jennifer A; Saul-McBeth, Jessica L; Iyer, Anita S et al. (2016) Quantitative and Functional Antibody Responses to the 13-Valent Conjugate and/or 23-Valent Purified Polysaccharide Vaccine in Aging HIV-Infected Adults. J AIDS Clin Res 7:|
|Leggat, David J; Iyer, Anita S; Ohtola, Jennifer A et al. (2015) Response to Pneumococcal Polysaccharide Vaccination in Newly Diagnosed HIV-Positive Individuals. J AIDS Clin Res 6:|
|Iyer, Anita S; Leggat, David J; Ohtola, Jennifer A et al. (2015) Response to Pneumococcal Polysaccharide Vaccination in HIV-Positive Individuals on Long Term Highly Active Antiretroviral Therapy. J AIDS Clin Res 6:|
|Iyer, Anita S; Ohtola, Jennifer A; Westerink, M A Julie (2015) Age-related immune response to pneumococcal polysaccharide vaccination: lessons for the clinic. Expert Rev Vaccines 14:85-97|
|Leggat, David J; Khaskhely, Noor M; Iyer, Anita S et al. (2013) Pneumococcal polysaccharide vaccination induces polysaccharide-specific B cells in adult peripheral blood expressing CD19?CD20?CD3?CD70?CD27?IgM?CD43?CD5?/?. Vaccine 31:4632-40|
|Westerink, M A Julie; Schroeder Jr, Harry W; Nahm, Moon H (2012) Immune Responses to pneumococcal vaccines in children and adults: Rationale for age-specific vaccination. Aging Dis 3:51-67|
|Khaskhely, Noor; Mosakowski, Jason; Thompson, Rebecca S et al. (2012) Phenotypic analysis of pneumococcal polysaccharide-specific B cells. J Immunol 188:2455-63|