Naturally SIV-infected sooty mangabeys (SMs) do not progress to AIDS despite high-level virus replication. We previously showed that the fraction of CD4+CCR5+ T-cells is lower in SMs compared to humans and macaques. Here we found that, after in vitro stimulation, SM CD4+ T-cells fail to up-regulate CCR5, and that this phenomenon is more pronounced in CD4+ central-memory T-cells (TCM). CD4+ T-cell activation was similarly uncoupled from CCR5 expression in SMs in vivo during (i) acute SIV infection and (ii) following antibody-mediated CD4+ T-cell depletion. Remarkably, CD4+ TCM of SMs that express low levels of CCR5 demonstrated reduced susceptibility to SIV infection both in vivo and in vitro when compared to CD4+ TCM of RMs. These data suggest that low CCR5 expression on SM CD4+ T-cells favors the preservation of CD4+ T-cell homeostasis and promotes an AIDS-free status by protecting CD4+ TCM from direct virus infection.

IntroductionThe pathogenesis of the immunodeficiency that occurs in HIVinfected humans and SIV-infected rhesus macaques (RMs) is the result of a complex and incompletely understood interaction between the virus and the host immune system. 1 The establishment of a state of chronic, generalized immune activation is a characteristic feature of pathogenic HIV/SIV infections in humans and RMs, with many different immune cell types showing an activated/ dysfunctional phenotype. 1 Importantly, the level of chronic immune activation represents a strong predictor of both disease progression and poor immunologic response to antiretroviral therapy. [2][3][4] Strong indirect support for the crucial role of immune activation in AIDS pathogenesis is provided by studies of SIV infections in African monkeys that are natural hosts for SIV, such as sooty mangabeys (SMs), in which levels of virus replication are similar or even higher to those found in HIV-infected humans, but are not sufficient to induce any signs of illness or progression to AIDS due, in part to the absence of increased levels of immune activation. 5 The exact mechanisms that sustain high levels of chronic immune activation in HIV-infected humans and SIVinfected RMs, or limit them in natural hosts for SIV, are still unclear, and their elucidation is considered a key priority in contemporary AIDS research. 6 CD4 ϩ T cells, the main target of HIV and SIV, are a relatively heterogeneous population of immune cells based on phenotype, cytokine profile, and functions. CD4 ϩ T cells can be phenotypically classified in broad subsets of naive, central memory, transitional memory, and effector memory T cells based on their differentiation status. 7 In addition, T helper (Th) can be classified into subsets that include Th1, Th2, Th17, T follicular helper (Tfh), and regulatory (Treg) cells based on their cytokine profile and/or functions. 8 Pathogenic HIV/SIV infections of humans and RMs are associated with major perturbations of the relative proportion of the different CD4 ϩ T-cell subsets. Interestingly, the in vivo changes induced by HIV/SIV infections on the homeostasis of CD4 ϩ T-cell subsets are different in natural and non-natural hosts for lentiviruses. [9][10][11] We and others have shown that intestinal Th17 cells are preferentially depleted in pathogenic HIV/SIV infections of humans and RMs, but maintained at a healthy frequency in nonprogressive SIV infection of SMs. 9,12,13 Th17 cells are essential for mucosal immunity as they respond to extracellular bacteria and fungi by recruiting neutrophils and inducing tight junctions, antibacterial defensin, and/or mucin expression, thus preserving the structural barrier of the gastrointestinal (GI) tract. 14,15 Consistent with this paradigm, the depletion of Th17 cells in HIV-infected humans and SIV-infected RMs is associated with loss of mucosal integrity and signs of microbial translocation, 9,13,16,17 whereas the preservation of a normal fraction of intestinal Th17 cells in SIV-infected SMs is associated with the mai...

We previously showed that human beta defensin-3 (hBD-3) activates mDC via TLR1/2. Here we investigated the effects of hBD-3 on NK cell activation state and effector functions. We observed that hBD-3 activates PBMC to secrete IFN-γ and kill K562 and HUH hepatoma target cells in an NK dependent fashion, and both TLR1/2 and CCR2 are involved. TLR1, TLR2 and CCR2 were expressed on NK cells, and in purified NK culture experiments we observed hBD-3 to directly act on NK cells, resulting in CD69 upregulation and IFNγ secretion. We also observed mDC-hBD-3 enhanced NK cytolytic activity and IFNγ production. These results implicate hBD-3 in its ability to directly activate NK cells and increase NK cell effector function, as well as promote mDC-dependent NK activity. HBD-3 may therefore act as a mediator of innate cell interactions that result in bridging of innate and adaptive immunity.

Approximately half of those with chronic hepatitis C virus (HCV) infection have circulating rheumatoid factor (RF), and a portion of these individuals develop cryoglobulinemic vasculitis. B cell phenotype/function in relation to RF in serum has been unclear. We examined B cell subset distribution, activation state (CD86), cell cycle state (Ki67), and ex-vivo response to BCR, TLR9 and TLR7/8 stimulation, in chronic HCV-infected donors with or without RF, and uninfected donors. Mature-activated B-cells of HCV-infected donors had lower CD86 expression compared to uninfected donors, and in the presence of RF they also showed reduced CD86 expression in response to BCR and TLR9 stimulation. Additionally, mature activated memory B cells of HCV RF+ donors less commonly expressed Ki67+ than HCV RF- donors, and did not proliferate as well in response to BCR stimulation. Proportions of mature-activated B cells were enhanced, while naïve B-cells were lower in the peripheral blood of HCV-RF+ compared to RF- and uninfected donors. None of these parameters normalize by week 8 of IFN free direct acting antiviral (DAA) therapy in HCV RF+ donors, while in RF- donors, mature activated B cell proportions did normalize. These data indicate that while chronic HCV infection alone results in a lower state of activation in mature activated memory B cells, the presence of RF in serum is associated with a more pronounced state of unresponsiveness and an overrepresentation of these B cells in the blood. This phenotype persists at least during the early time window after removal of HCV from the host.