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Determination of Parameters that Constitute an HIV-Specific Immune Response Associated with Disease Progression in a Perinatally HIV-Infected Pediatric Population

  • Author(s): Sharp, Elizabeth Ramona
  • Advisor(s): Nixon, Douglas
  • et al.
Abstract

Pediatric HIV infection is a major worldwide public-health challenge, with an estimated rate of 1,200 children being infected daily in sub-Saharan Africa alone. In spite of this, the HIV-specific immune response in perinatally infected children has been relatively understudied. These studies were designed to probe specific aspects of the immune response to HIV in a group of vertically infected children/adolescents, treated at the Jacobi Medical Center in the Bronx, NY. The first study investigated the association between ethnicity and HIV-specific CD8+ T cell responses. Using a cytokine-enhanced ELISpot assay to measure IFN-gamma secretion in response to stimulation by HIV proteins Gag, Nef, and Tat, we show that African-American subjects displayed an immune response of higher magnitude than age and disease-matched Hispanic subjects. With the second study, we focused on defects in monocytes, specifically the signaling within, resulting from HIV infection. We utilized a recently developed intracellular staining technique, phospho-flow, to investigate the Jak/Stat signaling pathway in the monocytes of HIV-infected children. We found significantly lower levels of Jak/Stat signaling in response to stimulation in HIV-infected individuals compared to non-infected individuals. The last study focused on immunodominance patterns and differentiation profiles of Gag-specific CD8+ T cell responses in two progression groups within the same cohort of perinatally infected children. Using CDC guidelines, we classified patients into those with no immunosuppression or with severe immunosuppression. Using the IFN-gamma ELISpot assay, we then identified all epitope-specific CD8+ T cell responses to the Gag protein and compiled the immunodominance hierarchy of each patient. Utilizing multi-parameter cytokine flow cytometry, we then identified the differentiation profile and cytokine secretion profile of each epitope-specific response. We found significant differences between the progression groups with respect to immunodominance hierarchies of Gag-specific CD8+ T cell responses as well as striking differences in the differentiation profiles of CD4+ T cells, specifically an accumulation of the CCR7-CD45RA+ subset. Taken together, these studies add to the field of pediatric HIV immune responses and identify several factors, namely race, monocyte defects, and immunodominance patterns, which can play an important role in the role of the immune response in progression of HIV disease in perinatally infected children.

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