e HLA-B*57, etc ), we interpret that NK

cells can contri

e. HLA-B*57, etc.), we interpret that NK

cells can contribute to both resistance against infection and to viral control once infected (Table 3). Together with data illustrating increased activation [10,20,91] and function [6,19] of NK cells in HESNs, these results suggest that NK cells fit the model of a candidate cell type whose retained function and heightened activation status may contribute to both control over HIV-1 replication and resistance to HIV-1 NVP-LDE225 in HESN subjects. The identification of highly exposed but persistently uninfected individuals that maintain resistance to HIV-1 infection despite high-risk exposure has generated hope that mechanisms of natural resistance to HIV-1 may some day be translated into a sterilizing vaccine to prevent infection. The failure of T cell vaccine strategies [34,35] and pre-existing CTL responses in HESN subjects to HIV-1 to protect against HIV-1 infection [38–40] has dampened interest

in the potential role of T cells in sterilizing immunity. Similarly, a recent study from Africa documenting an absence of consistent HIV-specific IgA responses in plasma or cervicovaginal lavage from HESN sex workers [59] is in agreement with previous findings indicating a lack of a direct correlation between HIV-resistance and IgA responses [60]. Collectively, the presence of HIV-specific selleck inhibitor humoral or cellular responses has not been a unifying functional attribute among HESN subjects, thereby highlighting the potential role of non-adaptive mechanisms of immunity in protection from HIV-1. Genotypic and functional association between increased NK activity and resistance to HIV-1 infection in multiple cohorts of HESN subjects suggests that the innate immune response may play a greater role than proposed to date in maintaining natural ZD1839 molecular weight resistance to infection in high-risk subjects. Alternatively, synergistic responses involving both the innate and adaptive immune compartments against HIV-1 may act in concert to resist infection with HIV-1. Examples of the co-operative response

between the adaptive and innate immune system include the targeting of MHC class I highly expressing cells by CD8 T cells and the targeting of MHC-class I down-regulated cells by NK cells. Similarly, HIV-specific IgA antibodies may act alone in neutralizing HIV-1 (dimeric IgA), or may increase HIV-1 clearance by binding to macrophages or neutrophils via the monomeric IgA Fc receptor, CD89 [56,57]. During chronic infection, HIV-specific IgGs are known to mediate neutralization of viral particles while also complementing well with NK cells to trigger antibody-mediated antibody-dependent cytotoxicity of infected target cells. Moving forward, non-human primate studies modelling HESN resistance to infection will be critical in investigating the complementary role of innate and adaptive immunity in resistance to HIV-1 infection. As shown in Fig.

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