Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells

Abstract

In early simian immunodeficiency virus (SIV) and human immunodeficiency virus-1 (HIV-1) infections, gut-associated lymphatic tissue (GALT), the largest component of the lymphoid organ system, is a principal site of both virus production and depletion of primarily lamina propria memory CD4+ T cells; that is, CD4-expressing T cells that previously encountered antigens and microbes and homed to the lamina propria of GALT. Here, we show that peak virus production in gut tissues of SIV-infected rhesus macaques coincides with peak numbers of infected memory CD4+ T cells. Surprisingly, most of the initially infected memory cells were not, as expected, activated but were instead immunophenotypically 'resting' cells that, unlike truly resting cells, but like the first cells mainly infected at other mucosal sites and peripheral lymph nodes, are capable of supporting virus production. In addition to inducing immune activation and thereby providing activated CD4+ T-cell targets to sustain infection, virus production also triggered an immunopathologically limiting Fas-Fas-ligand-mediated apoptotic pathway in lamina propria CD4+ T cells, resulting in their preferential ablation. Thus, SIV exploits a large, resident population of resting memory CD4+ T cells in GALT to produce peak levels of virus that directly (through lytic infection) and indirectly (through apoptosis of infected and uninfected cells) deplete CD4+ T cells in the effector arm of GALT. The scale of this CD4+ T-cell depletion has adverse effects on the immune system of the host, underscoring the importance of developing countermeasures to SIV that are effective before infection of GALT.

Intestinal double‐positive CD4+CD8+ T cells are highly activated memory cells with an increased capacity to produce cytokines

“…Finally, most DP cells in the intestine are memory cells. Memory CD4 + T cells have been shown to be selectively infected in SIV and HIV [1,[40][41][42]. Combined these observations support our earlier data suggesting that DP T cells in the intestine are rapidly eliminated in early SIV infection due to their increased expression of viral co-receptors and their higher level of activation [1].…”

Differential cross-reactivity of monoclonal antibody OPD4 (anti-CD45RO) in macaques

“…1) indicating that it does not exclusively label CD4+ T cells. Reactivity of this antibody in rhesus macaques of Indian origin by immunohistochemistry has previously been reported [1]. However, pigtailed macaques and rhesus macaques of Chinese origin are also widely used in research into these and other diseases.…”

“…The ability to distinguish naïve and memory subsets in macaques led to the discovery that simian immunodeficiency virus rapidly and selectively infects and eliminates "memory" CD4+ T cells, particularly in mucosal tissues [1][2][3], findings that were recently confirmed in HIV-infected patients [4,5]. These findings have revolutionized our understanding of HIV pathogenesis by demonstrating that HIV *Corresponding author: RS Veazey, Tulane National Primate Research Center, 18703 Three Rivers Road, Covington, LA 70433, Phone (985) 871-6228, Fax (985) 871-6510, Email: rveazey@tulane.edu.…”

“…While OPD4 has been shown to cross-react in rhesus macaques [1,15] its specificity has not been thoroughly examined in rhesus or other macaque species. In this study, we examined the reactivity, distribution, and specificity of OPD4 in rhesus macaques (Macaca mulatta) of both Chinese and Indian origin, as well as Pigtail macaques (Macaca nemestrina).…”

HIV-Associated Bacterial Pneumonia

“…As is the case in other tissues, it is the CD4/CXCR6 co-expressing T cells of the effector/memory phenotype which are most vulnerable [2,3]. HIV-mediated depletion of CD4 + T cells is a direct consequence of both productive virus infection [18] and induction of Fas-mediated apoptosis in both HIV-infected and -uninfected cells [19]. In addition to these direct mechanisms of HIV-induced T cell depletion, increasing evidence has implicated chronic activation of plasmacytoid DCs as being an indirect mechanism of T cell dysfunction and cytotoxicity [20,21].…”