Natural killer (NK) cells contribute to control of HIV/SIV infection. We defined macaque NK-cell subsets based on expression of CD56 and CD16 and found their distribution to be highly disparate. CD16 ؉ NK cells predominated in peripheral blood, whereas most mucosal NK cells were CD56 ؉ , and lymph nodes contained both CD56 ؉ and CD16 ؊ CD56 ؊ (doublenegative [DN]) subsets. Functional profiles were also distinct among subsets-CD16 ؉ NK cells expressed high levels of cytolytic molecules, and CD56 ؉ NK cells were predominantly cytokine-secreting cells, whereas DN NK possessed both functions. In macaques chronically infected with SIV, circulating CD16 ؉ and DN NK cells were expanded in number and, although markers of cytoxicity increased, cytokine secretion decreased. Notably, CD56 ؉ NK cells in SIV-infected animals up-regulated perforin, granzyme B, and CD107a. In contrast, the lymph nodehoming molecules CD62 ligand (CD62L) and C-C chemokine receptor type 7 (CCR7), which are expressed primarily on CD56 ؉ and DN NK cells, were significantly down-regulated on NK cells from infected animals. These data demonstrate that SIV infection drives a shift in NK-cell function characterized by decreased cytokine production, expanded cytotoxicity, and trafficking away from secondary lymphoid organs, suggesting that the NK-cell repertoire is not only heterogeneous but also plastic. IntroductionSince their discovery in the 1970s, natural killer (NK) cells have been considered the major effector cells of the innate immune system because of their ability to kill virus-infected or neoplastic cells. Although NK cell-mediated killing does not require prior antigen sensitization, cell-to-cell contact between NK and target T cells occurs through a complex array of inhibitory and activating receptors. In humans, NK cells express both killer-cell immunoglobulin-like receptors (KIRs), which interact with major histocompatibility complex (MHC) class I molecules and can be either inhibitory or activating, and receptors belonging to the C-type lectin family such as natural killer group 2A (NKG2A), an inhibitory receptor that recognizes HLA-E and NKG2D, which recognizes the stress-induced ligands MHC class I chain-related gene A and B (MICA/MICB) and members of the ULBP family. 1 Human NK cells also express various natural cytotoxicity receptors including NKp46, NKp30, and NKp44, for which the ligands remain incompletely characterized. 2,3 However, increasing evidence suggests that the complexity of NK-cell function has been underappreciated and that in addition to cytolysis of aberrant T cells, NK cells also produce a wide array of cytokines, mediate tolerance to self-antigens, and regulate dendritic cell functions. 4 Most recently, murine studies have suggested that NK cells may even display characteristics of adaptive immune responses. 5 In humans, 2 primary phenotypically defined subsets of NK cells have been described, cytolytic CD56 dim CD16 ϩ and cytokinesecreting CD56 bright CD16 Ϫ subsets, of which the CD56 dim CD16 ϩ subset predomina...

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These comprehensive data demonstrate modest (< twofold) mean reductions in didanosine and stavudine susceptibilities at follow-up. The emergence of zidovudine associated mutations in this retroviral-naive population treated with combination didanosine and stavudine therapy is notable. Furthermore, the emergence of these mutations and of the Q151 M multinucleoside resistance complex raise concerns for potential nucleoside analog cross-resistance. The potential mechanisms driving the selection of the zidovudine associated mutations in the setting of didanosine and stavudine therapy and the relevance of these findings to current three and four drug regimens merit further evaluation.

Nearly all human immunodeficiency virus (HIV) infections are acquired mucosally, and the gut-associated lymphoid tissues are important sites for early virus replication. Thus, vaccine strategies designed to prime virus-specific cytotoxic T lymphocyte (CTL) responses that home to mucosal compartments may be particularly effective at preventing or containing HIV infection. The Salmonella type III secretion system has been shown to be an effective approach for stimulating mucosal CTL responses in mice. We therefore tested ⌬phoP-phoQ attenuated strains of Salmonella enterica serovar Typhimurium and S. enterica serovar Typhi expressing fragments of the simian immunodeficiency virus (SIV) Gag protein fused to the type III-secreted SopE protein for the ability to prime virus-specific CTL responses in rhesus macaques. Mamu-A*01 ؉ macaques were inoculated with three oral doses of recombinant Salmonella, followed by a peripheral boost with modified vaccinia virus Ankara expressing SIV Gag (MVA Gag). Transient low-level CTL responses to the Mamu-A*01 Gag 181-189 epitope were detected following each dose of Salmonella. After boosting with MVA Gag, strong Gag-specific CTL responses were consistently detected, and tetramer staining revealed the expansion of Gag 181-189 -specific CD8 ؉ T-cell responses in peripheral blood. A significant percentage of the Gag 181-189 -specific T-cell population in each animal also expressed the intestinal homing receptor ␣4␤7. Additionally, Gag 181-189 -specific CD8 ؉ T cells were detected in lymphocytes isolated from the colon. Yet, despite these responses, Salmonella-primed/MVA-boosted animals did not exhibit improved control of virus replication following a rectal challenge with SIVmac239. Nevertheless, this study demonstrates the potential of mucosal priming by the Salmonella type III secretion system to direct SIV-specific cellular immune responses to the gastrointestinal mucosa in a primate model.