Immunologic and virologic assessments of anti-retroviral therapy in HIV-infected patients are mainly performed on peripheral blood sample. However, blood represents only 2% of the total lymphocytes in the body. Since the gut-associated lymphoid tissue (GALT) harbors the majority of T lymphocytes i the body. Thus, it is an important reservoir of HIV. Our knowledge of HIV suppression and immune restoration in intestinal mucosa during anti-retroviral therapy of HIV infection is limited. The overall objective of this application is to examine the immunologic and virologic effects of anti-retroviral therapy (PMPA) in GALT in comparison to peripheral lymph nodes and blood of simian immunodeficiency virus (SIV)-infected rhesus macaques, a primate model for AIDS. The applicants will test the hypothesis that the level of CD4+ T cell depletion and the stage of viral infection in T cell repopulation (flowcytometry), viral suppression (bDNA assay, PCR and in situ hybridization) and the emergence of viral genomic diversity and drug-resistant variants in intestinal tissue.
The Specific aim 1 will be to characterize the phenotype of CD4+ T cells repopulating intestinal mucosa of SIV-infected rhesus macaques following anti-retroviral therapy and to determine the mechanisms of the CD4+ T cell repopulation.
The specific aim 2 will be to determine the suppression of viral loads and to examine the emergence of genomic diversity and drug-resistant viral variants in intestinal tissues following anti-retroviral therapy in comparison to peripheral lymph nodes and blood.
The specific aim 3 will be to examine whether T cell activation by short-term IL-2 administration will alter the pool of virally infected cells in GALT of SIV-infected animals that are undergoing PMPA therapy. The applicant believes that the proposed studies will provide insights into the immunologic and virologic effects of anti-retroviral therapy in intestinal lymphoid tissue in comparison to peripheral blood and lymph nodes and that this information will be valuable in development of more effective anti-retroviral and immunomodulatory approaches.
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