title: Disruption of intestinal CD4+ T cell homeostasis is a key marker of systemic CD4+ T cell activation in HIV-infected individuals.
abstract: HIV infection is associated with depletion of intestinal CD4(+) T cells, resulting in mucosal immune dysfunction, microbial translocation, chronic immune activation, and progressive immunodeficiency. In this study, we examined HIV-infected individuals with active virus replication (n = 15), treated with antiretroviral therapy (n = 13), and healthy controls (n = 11) and conducted a comparative analysis of T cells derived from blood and four gastrointestinal (GI) sites (terminal ileum, right colon, left colon, and sigmoid colon). As expected, we found that HIV infection is associated with depletion of total CD4(+) T cells as well as CD4(+)CCR5(+) T cells in all GI sites, with higher levels of these cells found in ART-treated individuals than in those with active virus replication. While the levels of both CD4(+) and CD8(+) T cell proliferation were higher in the blood of untreated HIV-infected individuals, only CD4(+) T cell proliferation was significantly increased in the gut of the same patients. We also noted that the levels of CD4(+) T cells and the percentages of CD4(+)Ki67(+) proliferating T cells are inversely correlated in both blood and intestinal tissues, thus suggesting that CD4(+) T cell homeostasis is similarly affected by HIV infection in these distinct anatomic compartments. Importantly, the level of intestinal CD4(+) T cells (both total and Th17 cells) was inversely correlated with the percentage of circulating CD4(+)Ki67(+) T cells. Collectively, these data confirm that the GI tract is a key player in the immunopathogenesis of HIV infection, and they reveal a strong association between the destruction of intestinal CD4(+) T cell homeostasis in the gut and the level of systemic CD4(+) T cell activation.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Shari N
authors.initials: SN
authors.lastname: Gordon
authors.forename: Barbara
authors.initials: B
authors.lastname: Cervasi
authors.forename: Pamela
authors.initials: P
authors.lastname: Odorizzi
authors.forename: Randee
authors.initials: R
authors.lastname: Silverman
authors.forename: Faten
authors.initials: F
authors.lastname: Aberra
authors.forename: Gregory
authors.initials: G
authors.lastname: Ginsberg
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Estes
authors.forename: Mirko
authors.initials: M
authors.lastname: Paiardini
authors.forename: Ian
authors.initials: I
authors.lastname: Frank
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D002452:Cell Count; D049109:Cell Proliferation; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D007422:Intestines; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008297:Male; D008875:Middle Aged
chemical_list: D044966:Anti-Retroviral Agents