Simian immunodeficiency virus (SIV)–specific cytotoxic T lymphocytes in gastrointestinal tissues of chronically SIV-infected rhesus monkeys

Abstract

Although systemic virus-specific cytotoxic T lymphocyte (CTL) responses are of critical importance in controlling virus replication in individuals infected with human immunodeficiency virus 1 (HIV-1), little is known about this immune response in the gastrointestinal (GI) tract. This study investigated the GI tract CTL response in a nonhuman primate model for HIV-1 infection, simian immunodeficiency virus (SIV)-infected rhesus monkeys. Lymphocytes from duodenal pinch biopsy specimens were obtained from 9 chronically SIVmac-infected rhesus monkeys and GI tract lymphocytes were harvested from the jejunum and ileum of 4 euthanized SIVmac-infected rhesus monkeys. Lymphocytes were also assessed in GI mucosal tissues by in situ staining in histologic specimens. SIVmac Gagspecific CTLs were assessed in the monkeys using the tetramer technology. These GI mucosal tissues of chronically SIVmacinfected rhesus monkeys contained levels of CTLs comparable to those found in the peripheral blood and lymph nodes. The present studies suggest that the CD8 ؉ CTL response in GI mucosal sites is comparable to that seen systemically in SIVmac-infected rhesus monkeys. (Blood. 2001;98:3757-3761)

HIV infection and the gastrointestinal immune system

“…Indeed, several studies of rhesus macaques have demonstrated vaccine-induced functional SIV-specific CD8 T cells within the GI tract. 65,68,69 Moreover, the frequency of vaccine-induced SIV-specific CD8 T cells in the GI tract was negatively correlated with the peak viral load in plasma after challenge with the pathogenic SHIV-ku2, while there was no such correlation with the frequency of SIV-specific CD8 T cells in peripheral blood. 69 Although HIV-specific T-cell responses may reduce viral replication in vivo, the prevention of initial infection would likely require a mucosal humoral immune response.…”

“…42 Studies in humans examined only the frequency of HIV-specific CD8 T cells in rectal tissue, but studies of SIV-specific CD8 T cells with peptide-major histocompatibility complex tetramers have demonstrated that SIV-specific CD8 T cells can be detected in the upper and lower small intestine. 65 However, these studies did not examine the functional capacity of HIV/SIV-specific CD8 T cells in the GI tract. Indeed, in the peripheral blood of HIV-infected individuals, some HIVspecific CD8 T cells that control viral replication and maintain peripheral blood CD4 T cells are found to produce multiple effector cytokines, including IFN-γ, macrophage-inflammatory protein-1β, TNF-α, and IL-2; they maintain the ability to degranulate (measured by surface mobilization of CD107a).…”

High frequencies of polyfunctional HIV-specific T cells are associated with preservation of mucosal CD4 T cells in bronchoalveolar lavage

“…13,33 In addition, Mamu A01 + rhesus macaques attain significantly lower set point VLs after SIV infection compared to rhesus macaques that do not express the A01 allele, 34 and these monkeys manifest high frequencies of Mamu-A01-restricted SIV-specific CD8 T cells in both small and large intestines. [35][36][37] Moreover, Mamu-A01 + rhesus macaques that fail to control viral replication lack functional SIV-specific CD8 T cells in mucosal sites. 35 Alternatively, local HIV-specific T-cell responses in BAL may suppress viral replication by direct anti-viral effector mechanisms including cytolysis of infected cells and secretion of antiviral chemokines and cytokines.…”

High Frequency of Virus-Specific CD8+T Cells in the Central Nervous System of Macaques Chronically Infected with Simian Immunodeficiency Virus SIVmac251

“…The frequency of these CTLs during chronic SIV infection in different compartments varies among animals (12). However, for the majority of chronically infected animals, the frequencies of this response are comparable in peripheral blood and lymph nodes and have often been found to be higher in the gastrointestinal and urogenital tissues, spleen, bone marrow, and liver (12,41). Here we demonstrate that in all the Mamu-A*01-positive macaques studied, larger numbers of Gag 181-189 CM9-specific CTLs could be found in the CNS than in peripheral blood (Fig.…”

“…The levels of tetramer-binding cells with this Gag specificity in peripheral blood, spleen, lymph nodes, bone marrow, liver, and gastrointestinal and urogenital tracts of acutely and chronically SIVmac251-infected macaques have already been extensively analyzed (12,24,41,42,45). For Mamu-A*01-positive macaques, Gag 181-189 CM9 tetramerpositive CD8 ϩ T cells emerge in blood at week 2 to 3 after exposure to SIVmac251 and are found as early as 4 weeks postinoculation in secondary and tertiary lymphoid organs (13,24).…”