In recent years, loss of CD4 T cells from the gut of HIV-positive people has become a major research focus. Gut CD4 T cell depletion happens rapidly after infection, and many studies have suggested that recovery of these cells is typically limited even after prolonged antiretroviral therapy (ART). However, the bleakest data has been obtained by measuring the percentage of CD4 T cells in the gut relative to other lymphocytes, and this can produce misleading results because CD8 T cell numbers are increased in the setting of HIV infection.
A new paper from Irini Sereti’s laboratory at NIAID reports that the picture is far more encouraging when absolute numbers of CD4 T cells are measured. Taking samples from both the colon and terminal ileum, the researchers show that absolute CD4 T cell numbers among people on long-term (>5 years) ART with viral loads less than 50 copies are comparable to uninfected controls. The numbers are expressed as CD4 T cells per gram of tissue and the results for the ART-treated vs. control group were as follows: 3.9x106 vs. 3.6x106 (colon) and 1.0x106 vs. 1.6x106 (terminal ileum). The researchers note that in some prior papers, “the persistence of a high proportion of CD8 T cells in HIV-infected patients appeared to result in an underestimation of CD4 T cell reconstitution…our findings are in agreement with recent studies using both immunohistochemistry and flow cytometric analyses; some of these have suggested that gut CD4 T-cell reconstitution may even exceed what occurs in peripheral blood.”
The researchers also write: “It has also been proposed that initiating ART therapy during acute infection may result in more rapid and complete reconstitution of the CD4 T-cell population in the gut. Three of the four patients in this study who reconstituted their CD4 T-cell counts in the colon to values higher than the median of the HIV-uninfected group had peripheral nadir CD4+ T-cell counts of less than 250 cells per microliter. This suggests that CD4 T-cell restoration may occur despite substantial disease progression before ART initiation.”
Mucosal Immunology (2010) 3, 172–181; doi:10.1038/mi.2009.129; published online 2 December 2009
E J Ciccone1, S W Read2, P J Mannon3, M D Yao4, J N Hodge1, R Dewar5, C L Chairez1, M A Proschan6, J A Kovacs7 and I Sereti1
1. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA 2. The Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA 3. Division of Gastroenterology and Hepatology, University of Alabama-Birmingham, Birmingham, Alabama, USA 4. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA 5. SAIC-Frederick Inc., Frederick, Maryland, USA 6. The Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA 7. The Critical Care Medicine Department, NIH, Bethesda, Maryland, USA
The gut mucosa is an important site of HIV immunopathogenesis with severe depletion of CD4+ T cells occurring during acute infection. The effect of prolonged anti-retroviral therapy (ART) on cycling and restoration of T lymphocytes in the gut remains unclear. Colon and terminal ileal biopsies and peripheral blood samples were collected from viremic, untreated, HIV-infected participants, patients treated with prolonged ART (>5 years), and uninfected controls and analyzed by flow cytometry. In the gut, the proportion of cycling T cells decreased and the number of CD4+ T cells normalized in treated patients in parallel with β7 expression on CD4+ T cells in blood. Cycling of gut T cells in viremic patients was associated with increased plasma LPS levels, but not colonic HIV–RNA. These data suggest that gut T-cell activation and microbial translocation may be interconnected whereas prolonged ART may decrease activation and restore gut CD4+ T cells.
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