Mechanisms of Gastrointestinal CD4⁺T-Cell Depletion during Acuteand Early Human Immunodeficiency Virus Type 1 Infection

Abstract

During acute and early human immunodeficiency virus type 1 (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. A total of 32 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 by using real-time PCR. The phenotype of infected cells was characterized by using combinations of immunohistochemistry and in situ hybridization. Markers of immunological memory, activation, and proliferation were examined by flow cytometry and immunohistochemistry, and the hostderived cytotoxic cellular response was examined by using immunohistochemistry. GI CD4 ؉ T cells harbored, on average, 13-fold higher HIV-1 viral DNA levels and 10-fold higher HIV-1 RNA levels than PB CD4 ؉ T cells during AEI. HIV-1 RNA was detected in both "activated" and "nonactivated" mucosal CD4

The integrin α 4 β 7 forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1

“…Any replication advantage that HIV-1 can gain during the early stages of infection can have a significant impact on the efficiency of transmission. Although resting cells are thought to be the first cells infected, activated cells are critical to propagation and dissemination following sexual transmission (5,6,22). In this regard ␣ 4 ␤ 7 mediates the migration of CD4 ϩ T cells between Peyer's patches, mesenteric lymph nodes, and lamina propria (12,23), sites that represent a ''target rich'' environment for HIV-1.…”

“…These three gut-associated lymphoid tissues (GALT) play central roles in the initial phases of infection following sexual transmission. Antigen-specific ␣ 4 ␤ 7 ϩ CD4 ϩ T cells are also found in genital mucosa (3,4), where CD4 ϩ T cells are first infected (5,6). Within days following sexual transmission, infected cells migrate from the genital mucosa to Peyer's patches and mesenteric lymph nodes where high-level HIV replication occurs (5).…”

Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

“…Until recently, the magnitude of CD4 + T-cell depletion and its consequence were not fully appreciated. Initial studies in 1998 using an SIV model described a profound depletion of CD4 + T cells in both the gut and gut-associated lymphoid tissue (GALT) [66,67], and more recent studies have described a similar depletion in the gut of HIV-1 infected individuals [68][69][70][71]. The importance of these findings is underscored by the fact that between 60-80% of the total CD4 + T cell population resides in the gut associated lymphoid tissue [72].…”

HIV-1 Pathogenesis: The Virus

“…In cell culture HIV-1 infects activated cells with much greater efficiency than quiescent cells (Korin and Zack 1998), with central and effector memory cells as the primary targets (Pfaff et al 2010). However, in vivo there appears to be a type of CD4 þ T cell that does not express surface activation markers but supports significant levels of infection, particularly in the gut mucosa (Veazey et al 2000;Brenchley et al 2004b;Li et al 2005;Mattapallil et al 2005;Mehandru et al 2007).…”

“…The CD4 þ T cells in this tissue are rapidly depleted in primary infection, more so than in the blood or other lymphoid sites. Curiously, the cells that are depleted are in more of a resting state rather than an activated state, but none-the-less able to support robust viral replication (Li et al 1999;Veazey et al 2000;Mehandru et al 2007). Massive and early damage to the GALT is proposed to contribute to damage to the intestinal lining, which results in the translocation of bacterial products to the blood where they have the potential to enhance the generalized immune activation that is a central feature of HIV disease (see Lackner et al 2011).…”