In pathogenic HIV and SIV infections of humans and rhesus macaques (RMs), preferential depletion of CD4+ Th17 cells correlates with mucosal immune dysfunction and disease progression. Interleukin (IL)-21 promotes differentiation of Th17 cells, long-term maintenance of functional CD8+ T cells, and differentiation of memory B cells and antibody-secreting plasma cells. We hypothesized that administration of IL-21 will improve mucosal function in the context of pathogenic HIV/SIV infections. To test this hypothesis, we infected 12 RMs with SIVmac239 and at day 14 post-infection treated six of them with rhesus rIL-21-IgFc. IL-21-treatment was safe and did not increase plasma viral load or systemic immune activation. Compared to untreated animals, IL-21-treated RMs showed (i) higher expression of perforin and granzyme B in total and SIV-specific CD8+ T cells and (ii) higher levels of intestinal Th17 cells. Remarkably, increased levels of Th17 cells were associated with reduced levels of intestinal T cell proliferation, microbial translocation and systemic activation/inflammation in the chronic infection. In conclusion, IL-21-treatment in SIV-infected RMs improved mucosal immune function through enhanced preservation of Th17 cells. Further preclinical studies of IL-21 may be warranted to test its potential use during chronic infection in conjunction with antiretroviral therapy.

In rhesus macaques (RMs), experimental depletion of CD4+ T-cells prior to SIV infection results in higher viremia and emergence of CD4-independent SIV-envelopes. In this study we used the rhesus recombinant anti-CD4 antibody CD4R1 to deplete RM CD4+ T-cells prior to SIVmac251 infection and investigate the sources of the increased viral burden and the lifespan of productively infected cells. CD4-depleted animals showed (i) set-point viral load two-logs higher than controls; (ii) macrophages constituting 80% of all SIV vRNA+ cells in lymph node and mucosal tissues; (iii) substantial expansion of pro-inflammatory monocytes; (iv) aberrant activation and infection of microglial cells; and (v) lifespan of productively infected cells significantly longer in comparison to controls, but markedly shorter than previously estimated for macrophages. The net effect of CD4+ T-cell depletion is an inability to control SIV replication and a shift in the tropism of infected cells to macrophages, microglia, and, potentially, other CD4-low cells which all appear to have a shortened in vivo lifespan. We believe these findings have important implications for HIV eradication studies.

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...

While previous studies have shown that CD4+ T cells expressing CCR6 and CD161 are depleted from blood during HIV infection, the mechanisms underlying their loss remain unclear. In this study, we investigated how the homeostasis of CCR6+ and CD161+ CD4+ T cells contributes to SIV disease progression and the mechanisms responsible for their loss from circulation. By comparing SIV infection in rhesus macaques (RMs) and natural host sooty mangabeys (SMs), we found that the loss of CCR6+ and CD161+ CD4+ T cells from circulation is a distinguishing feature of progressive SIV infection in RMs. Furthermore, while viral infection critically contributes to the loss of CD161+CCR6-CD4+ T cells, a redistribution of CCR6+CD161− and CCR6+CD161+CD4+ T cells from the blood to the rectal mucosa is a chief mechanism for their loss during SIV infection. Finally, we provide evidence that the accumulation of CCR6+CD4+ T cells in the mucosa is damaging to the host by demonstrating their reduction from this site following initiation of antiretroviral therapy in SIV-infected RMs and their lack of accumulation in SIV-infected SMs. These data emphasize the importance of maintaining CCR6+ and CD161+ CD4+ T cell homeostasis, particularly in the mucosa, to prevent disease progression during pathogenic HIV/SIV infection.