HIV is now known to induce massive depletion of CD4+,CCR5+, memory T cells in the Gut Associated Lymphocyte Tissue (GALT) in macaques and humans within weeks following primary infection. Brenchley et al recently proposed that the microbial translocation of bacterial products into the systemic circulation from the gut in the wake of this massive T cell depletion may be a primary factor driving the persistent immune activation which characterizes chronic HIV infection. Most of the data supporting this hypothesis is cross-sectional and was obtained from adult patients. This study will determine whether there is a longitudinal correlation between increased levels of markers of microbial translocation and persistent immune activation in perinatally infected children. More specifically, it will determine whether increased circulating levels of lipopolysaccaride (LPS) and 16Sribosomal DNA(2 bacterial products) correlate with increased immune activation as evidenced by enhanced expression of the following markers: CD8+CD38+HLA-DR+, CD8+, CD38+, CD8+ HLA-DR+ T cells, and soluble CD14. Any specimen that has measurable 16SrDNA will also undergo qualitative 16SrRNA genomic amplification to determine what bacterial genus/species are being translocated. It will also determine whether there is a decline in the levels of these markers of microbial translocation which correlates with the decline in immune activation following the initiation of antiretroviral therapy. Recent evidence has also suggested that disturbances in the bacterial gut flora adversely affect adaptive immunity. To investigate this possibility which might further exacerbate the effects of microbial translocation by favoring the growth of more pathogenic species versus the usual symbiotic flora, this study will also determine whether there are significant differences in the proportions of major bacterial divisions comprising the enteric flora of HIV infected versus HIV uninfected children using the same 16SrRNA genomic amplification to characterize the microbial flora. If a correlation between the markers of microbial translocation and immune activation is confirmed and alterations in the microbial community that comprises the gut flora is detected, then a greater understanding of HIV pathogenesis may be gained and another potential therapeutic target identified;one that might allow us to disrupt the continuing cycle of immune activation that promotes HIV disease progression.

Public Health Relevance

If a correlation between the markers of microbial translocation and immune activation is confirmed and alterations in the microbial community that comprises the gut flora is detected, then a greater understanding of HIV pathogenesis may be gained and another potential therapeutic target identified;one that might allow us to disrupt the continuing cycle of immune activation that promotes HIV disease progression.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI091521-04
Application #
8712339
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Miller, Judith A
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Coral Gables
State
FL
Country
United States
Zip Code
33146