SAMHD1 restricts human immunodeficiency virus-1 (HIV-1) infection of dendritic and other myeloid cells at an early stage in the replication cycle. SIVsm/HIV-2 lineage viruses counteract SAMHD1-mediated restriction by encoding Vpx, a virion-packaged accessory protein that targets SAMHD1 for degradation. We show that SAMHD1 restricts HIV-1 infection of monocyte-derived macrophages (MDM) by hydrolyzing the cellular deoxynucleotide triphosphates (dNTP), reducing their level to below that required for the synthesis of the viral genomic DNA. Vpx prevented the SAMHD1-mediated decrease in dNTP. The restriction was partially alleviated in MDM by the addition of exogenous deoxynucleosides. HIV-1 with a V148I mutation in reverse transcriptase that lowers its affinity for dNTP was particularly sensitive to SAMHD1-mediated restriction. Nucleotide starvation could serve as a mechanism to protect cells from infection by a wide variety of infectious agents that replicate through a DNA intermediate.

Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naïve T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.

Some rare HIV-1-infected individuals, referred to as HIV controllers (HIC), have persistently undetectable plasma viral load in the absence of therapy. This control of HIV-1 replication has been associated with a strong, multifunctional specific CD8 ؉ T cell response. However, no direct link between this immune response and the control of viremia has so far been provided. We investigated parameters of specific CD8 ؉ T cell response and in vitro susceptibility to HIV-1 infection in 11 HIC. We found high frequencies of HIV-specific CD8 ؉ T cells. Interestingly, these cells expressed the activation marker HLA-DR but not CD38. This unique phenotype differentiates HIV-specific CD8 ؉ T cells from HIC and noncontroller subjects and likely reflects a high potential to expand upon exposure to antigen and a capacity to exert effector functions. Accordingly, although CD4 ؉ T cells from HIC were fully susceptible to HIV-1 superinfection, their CD8 ؉ T cells effectively suppressed HIV-1 infection. Remarkably, this potent anti-HIV activity was observed without prior stimulation of CD8 ؉ T cells. This activity was not mediated by secreted inhibitory factors but was due to the elimination of infected CD4 ؉ T cells and was observed only with autologous CD4 ؉ T cells, indicating an HLA-restricted cytotoxic mechanism. This constitutive antiviral capacity of CD8 ؉ T cells could account for the control of viral replication in HIC.HIV suppression ͉ CD8 ϩ T cells ͉ HLA-DR ͉ CD38

CD8 ؉ T cells are major players in the immune response against HIV. However, recent failures in the development of T cell-based vaccines against HIV-1 have emphasized the need to reassess our basic knowledge of T cell-mediated efficacy. CD8 ؉ T cells from HIV-1-infected patients with slow disease progression exhibit potent polyfunctionality and HIVsuppressive activity, yet the factors that unify these properties are incompletely understood. We performed a detailed study of the interplay between T-cell functional attributes using a bank of HIVspecific CD8 ؉ T-cell clones isolated in vitro; this approach enabled us to overcome inherent difficulties related to the in vivo heterogeneity of T-cell populations and address the underlying determinants that synthesize the qualities required for antiviral efficacy. Conclusions were supported by ex vivo analysis of HIV-specific CD8 ؉ T cells from infected donors. We report that attributes of CD8 ؉ T-cell effi- IntroductionCD8 ϩ T cells are essential for effective immunity against HIV-1, and the induction of such responses using vaccines has become a major objective in the strategy to halt the pandemic. 1 However, the recent outcome of the Merck STEP study, the most ambitious trial of an anti-HIV T cell-based vaccine conducted to date, has been a major disappointment. 2 Despite its immunogenicity, the vaccine failed both to prevent infection of vaccinated volunteers at high risk of acquiring HIV and to reduce viral load set points in infected vaccinees. This failure has roused the scientific community to step back and reconsider its basic knowledge of T cell-mediated efficacy. 3,4 Indeed, consensual opinion is that our general understanding of T-cell efficacy in HIV-1 infection is actually still limited, which represents a clear obstacle to the design of successful vaccines.Over recent years, qualitative attributes of CD8 ϩ T cells have increasingly become the focus of attempts to identify reliable correlates of immune protection against HIV. Among these, polyfunctionality 5 and HIV-suppressive activity 6 have been associated with spontaneous control of HIV infection and slower disease progression rates in infected patients. Of note, polyfunctionality is currently seen as the best correlate of T-cell efficacy measurable directly ex vivo. 7 Polyfunctional CD8 ϩ T cells are those that exhibit multiple effector functions (ie, degranulation and production of antiviral factors) simultaneously upon antigen encounter; this can be assessed after stimulation with cognate peptides by multiparametric flow cytometry (eg, mobilization of CD107 and intracellular production of interferon [IFN]-␥, tumor necrosis factor [TNF]-␣, interleukin-2 [IL-2], and macrophage-inflammatory protein [MIP]-1␤). 5 HIV-suppressive activity reflects the capacity of HIV-specific CD8 ϩ T cells to eliminate HIV-infected targets via classical class I major histocompatibility complex (MHC)-restricted cytotoxic lysis. 6,8 It can be assessed using primary CD4 ϩ T cells infected in vitro with HIV in the presence of...

“HIV controllers” (HICs) are rare individuals in whom HIV-1 plasma viral load remains undetectable without antiretroviral treatment. This spontaneous viral control in HICs is usually associated to strong functional HIV-specific CD8+ T cell responses. Accordingly, we have recently shown that CD8+ T cells from HICs strongly suppress ex vivo HIV-1 infection of autologous CD4+ T cells, suggesting a crucial role of this response in vivo. Knowledge of the mechanisms underlying the CD8+ T cell antiviral activity might help to develop effective T cell-based vaccines. In the present work, we further characterized the HIV-suppressive capacity of CD8+ T cells in 19 HICs. CD8+ T cells from 14 of the 19 HICs showed strong HIV-suppressive capacity ex vivo. This capacity was stable over time and was partially effective even on other primate lentiviruses. HIV-suppressive capacity of CD8+ T cells correlated strongly with the frequency of HIV-specific CD8+ T cells, and in particular of Gag-specific CD8+ T cells. We also identified five HICs who had weak HIV-suppressive CD8+ T cell capacities and HIV-specific CD8+ T cell responses. Among these five HICs, at least three had highly in vitro replicative viruses, suggesting that the control of viremia in these patients is not due to replication-defective viruses. These results, on the one hand, suggest the importance of Gag responses in the antiviral potency of CD8+ T cells from HICs and, on the other hand, propose that other host mechanisms may contribute to restraining HIV infection in HICs.