Brenchley JM, Schacker TW, Ruff, LE, et al. J Exp Med. 2004;200:749–759
Purpose of the Study.
Mechanisms underlying T-cell depletion in HIV infection are not well understood. This depletion has been studied primarily in the peripheral blood and, to some extent, in peripheral lymphoid tissue. However, a large fraction of CD4+ T cells reside in the gastrointestinal tract. The purpose of this study was to identify the effects of HIV infection on activation and depletion of T cells in the peripheral blood, gastrointestinal tract, and lymph nodes.
A total of 14 antiretroviral therapy–naive HIV-infected individuals and 7 HIV-uninfected individuals were recruited.
Peripheral blood mononuclear cells were obtained from venous blood, ileal Peyer’s patches and lamina propria samples were acquired by endoscopy and biopsy, and inguinal lymph nodes were obtained by percutaneous biopsy. Flow-cytometric analysis was conducted on specimens with standard techniques. HIV-specific T cells were analyzed for phenotypic markers. Additional studies were performed for HIV-specific CD8+ T cells and levels of collagen deposition within lymph nodes.
During primary HIV infection, preferential depletion of mucosal CD4+ T cells occurs compared with peripheral blood and lymph nodes. At all stages of HIV disease, most CD4+ T-cell depletion occurs in the gastrointestinal tract. The primary targets for depletion are activated CD4+CCR5+ T cells. Finally, T-cell activation in lymph nodes is associated with abnormal collagen deposition.
These findings define the nature and extent of CD4+ T-cell depletion in lymphoid tissue, particularly that of the gastrointestinal tract. Most CD4+ T-cells in the effector sites of the gastrointestinal tract are activated and express CCR5. This circumstance creates a particularly attractive medium for HIV infection and replication, which occurs most efficiently in activated CCR5+CD4+ T cells. Additionally, it was shown that therapeutic suppression of HIV permits recovery of circulating CD4+ T cells but did not restore CD4+ T cells in the gastrointestinal tract.
Intestinal CD4+ T cells are depleted selectively and rapidly in HIV-infected patients. These findings reflect earlier studies in simian immunodeficiency virus–infected macaque monkeys (Science. 1998;280:142–431). All of these studies together demonstrate that HIV induces severe, organ-specific T-cell depletion in a much briefer time frame than previously identified. Although clinical immunodeficiency may not be apparent for months to years after initial infection, it is clear that immune compromise occurs very early in the diseases process. Of great importance is the failure of long-term (≥5 years) highly active retroviral therapy to reverse this site-specific T-cell depletion. Additionally, other studies have demonstrated that HIV is consistently detectable in the intestine of HIV-infected patients, even those with no detectable plasma virus. Current therapies are inadequate for clearing the virus from the intestine, a major reservoir of HIV. New therapies aimed at the mucosal immune system will be required to address this issue. Finally, because the intestine is the earliest target for virus infection and T-cell loss, enhancing mucosal immunity will be critical for any vaccine strategy to be effective.