Trafficking of Human Immunodeficiency Virus Type 1-Specific CD8+T Cells to Gut-Associated Lymphoid Tissue during Chronic Infection

Abstract

Gut-associated lymphoid tissue (GALT) is a significant but understudied lymphoid organ, harboring a majority of the body's total lymphocyte population. GALT is also an important portal of entry for human immunodeficiency virus (HIV), a major site of viral replication and CD4⁺ T-cell depletion, and a frequent site of AIDS-related opportunistic infections and neoplasms. However, little is known about HIV-specific cell-mediated immune responses in GALT. Using lymphocytes isolated from rectal biopsies, we have determined the frequency and phenotype of HIV-specific CD8⁺ T cells in human GALT. GALT CD8⁺ T cells were predominantly CD45RO⁺ and expressed CXCR4 and CCR5. In 10 clinically stable, chronically infected individuals, the frequency of HIV Gag (SL9)-specific CD8⁺ T cells was increased in GALT relative to peripheral blood mononuclear cells by up to 4.6-fold, while that of cytomegalovirus (CMV)-specific CD8⁺ T cells was significantly reduced (P = 0.012). Both HIV- and CMV-specific CD8⁺ T cells in GALT expressed CCR5, but only HIV-specific CD8⁺ T cells expressed αΕβ7 integrin, suggesting that mucosal priming may account for their retention in GALT. Chronically infected individuals exhibited striking depletion of GALT CD4⁺ T cells expressing CXCR4, CCR5, and αΕβ7 integrin, but CD4⁺/CD8⁺ T-cell ratios in blood and GALT were similar. The percentage of GALT CD8⁺ T cells expressing αΕβ7 was significantly decreased in infected individuals, suggesting that HIV infection may perturb lymphocyte retention in GALT. These studies demonstrate the feasibility of using tetramers to assess HIV-specific T cells in GALT and reveal that GALT is the site of an active CD8⁺ T-cell response during chronic infection.