Posted by: Indonesian Children | August 15, 2009

Mechanisms of Gastrointestinal CD4+ T Cell Depletion During Acute and Early HIV-1 Infection

J. Virol. doi:10.1128/JVI.01739-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Mechanisms of Gastrointestinal CD4+ T Cell Depletion During Acute and Early HIV-1 Infection

Saurabh Mehandru, Michael A. Poles, Klara Tenner-Racz, Victoria Manuelli, Patrick Jean-Pierre, Peter Lopez, Anita Shet, Andrea Low, Hiroshi Mohri, Daniel Boden, Paul Racz, and Martin Markowitz*

Aaron Diamond AIDS Research Center and Rockefeller University, New York, NY 10016; New York University School of Medicine, Department of Medicine, Division of Gastroenterology, New York, NY 10016; Bernhard-Nocht Institut Fur Tropenmedizin, 20359 Hamburg, Germany

 

* To whom correspondence should be addressed. Email: mmarkowitz@adarc.org .

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Abstract

During acute and early HIV-1 infection (AEI) more than 50% of CD4+T cells are preferentially depleted from the gastrointestinal (GI) lamina propria. To better understand the underlying mechanisms, we studied virological and immunological events within the peripheral blood (PB) and GI tract during AEI. Thirty-two AEI subjects and 18 uninfected controls underwent colonic biopsy. HIV-1 viral DNA and RNA levels were quantified in CD4+ T cells derived from the GI tract and PB using real time polymerase chain reaction (PCR). The phenotype of infected cells was characterized using combinations of immunohistochemistry and in-situ hybridization. Markers of immunological memory, activation and proliferation were examined using flow-cytometry and immunohistochemistry and host-derived cytotoxic cellular response was examined using immunohistochemistry. GI CD4+ T cells harbored on average, 13-fold greater HIV-1 viral DNA levels and 10-fold greater HIV-1 RNA levels compared to PB CD4+ T cells during AEI. HIV-1 RNA was detected in both ‘activated’ and ‘non-activated’ mucosal CD4+ T cells. A significantly higher number of activated and proliferating T cells were detected in the GI tract compared to the PB and, a robust cytotoxic response (HIV-1 specificity not determined) was detected in the GI tract, as early as 18 days post infection. Mucosal CD4+ T cell depletion is multifactorial. Direct viral infection likely accounts for the earliest loss of CD4+ T cells. Subsequently, ongoing infection of susceptible CD4+ T cells along with activation induced cellular death and host cytotoxic cellular response are responsible for persistence of the lesion.

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