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

HIV-2 is less pathogenic for humans than HIV-1 and might provide partial cross-protection from HIV-1-induced pathology. Although both viruses replicate in the T cells of infected patients, only HIV-2 replicates efficiently in dendritic cells (DCs) and activates innate immune pathways. How HIV is sensed in DC is unknown. Capsid-mutated HIV-2 revealed that sensing by the host requires viral cDNA synthesis, but not nuclear entry or genome integration. The HIV-1 capsid prevented viral cDNA sensing up to integration, allowing the virus to escape innate recognition. In contrast, DCs sensed capsid-mutated HIV-1 and enhanced stimulation of T cells in the absence of productive infection. Finally, we found that DC sensing of HIV-1 and HIV-2 required the DNA sensor cGAS. Thus, the HIV capsid is a determinant of innate sensing of the viral cDNA by cGAS in dendritic cells. This pathway might potentially be harnessed to develop effective vaccines against HIV-1.

HIV infection results in CD4

The persistence of the HIV reservoir in infected individuals is a major obstacle to the development of a cure for HIV. Here, using an in vitro model of HIV-infected quiescent CD4 T cells, we reveal a gene expression signature of 103 upregulated genes that are specific for latently infected cells, including genes for 16 transmembrane proteins. In vitro screening for surface expression in HIV-infected quiescent CD4 T cells shows that the low-affinity receptor for the immunoglobulin G Fc fragment, CD32a, is the most highly induced, with no detectable expression in bystander cells. Notably, productive HIV-1 infection of T-cell-receptor-stimulated CD4 T cells is not associated with CD32a expression, suggesting that a quiescence-dependent mechanism is required for its induction. Using blood samples from HIV-1-positive participants receiving suppressive antiretroviral therapy, we identify a subpopulation of 0.012% of CD4 T cells that express CD32a and host up to three copies of HIV DNA per cell. This CD32a reservoir was highly enriched in inducible replication-competent proviruses and can be predominant in some participants. Our discovery that CD32a lymphocytes represent the elusive HIV-1 reservoir may lead to insights that will facilitate the specific targeting and elimination of this reservoir.

“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.

Human immunodeficiency virus (HIV) controllers are rare individuals who spontaneously control HIV type 1 replication for 10 years or more in the absence of antiretroviral treatment. In the present study, HIV controllers (n ‫؍‬ 11) maintained potent HIV-specific CD4 responses in spite of very low antigenic loads. Their CD4؉ central memory T (T CM ) cells were characterized by near-normal numbers and preserved interleukin-2 (IL-2) secretion in response to HIV antigens and uniformly high expression of the survival receptor IL-7 receptor ␣ (IL-7R␣). Controllers expressed CCR7 at higher levels than uninfected controls, suggesting differences in T CM -cell homing patterns. CD4؉ effector memory T (T EM )-cell responses were polyfunctional in HIV controllers, while IL-2 secretion was lost in viremic patients. Cytokine production was three times higher in controllers than in treated patients with undetectable viral loads, suggesting an intrinsically more efficient response in the former group. The total CD4؉ T EM -cell pool underwent immune activation in controllers, as indicated by increased HLA-DR expression, decreased IL-7R␣ expression, a bias towards gamma interferon production upon polyclonal stimulation, and increased macrophage inflammatory protein 1␤ secretion associated with chronic CCR5 down-regulation. Thus, HIV controllers showed a preserved CD4؉ T CM -cell compartment and signs of potent functional activation in the CD4؉ T EM -cell compartment. While controllers did not show the generalized immune activation pattern associated with disease progression, they had signs of immune activation restricted to the effector compartment. These findings suggest the induction of an efficient, nondetrimental type of immune activation in patients who spontaneously control HIV.

Primary viral infections, including primary HIV infection, trigger intense activation of the immune system, with marked expansion of CD38(+)CD8(+) T cells. Whether this expansion involves only viral-specific cells or includes a degree of bystander activation remains a matter of debate. We therefore examined the activation status of EBV-, CMV-, and influenza virus (FLU)-specific CD8(+) T cells during primary HIV infection, in comparison to HIV-specific CD8(+) T cells. The activation markers CD38 and HLA-DR were strongly expressed on HIV-specific CD8(+) T cells. Surprisingly, CD38 expression was also up-regulated on CD8(+) T cells specific for other viruses, albeit to a lesser extent. Activation marker expression returned to normal or near-normal values after 1 year of highly active antiretroviral therapy. HIV viral load correlated with CD38 expression on HIV-specific CD8(+) T cells but also on EBV-, CMV-, and FLU-specific CD8(+) T cells. In primary HIV infection, EBV-specific CD8(+) T cells also showed increased Ki67 expression and decreased Bcl-2 expression, compared with values observed in HIV-seronegative control subjects. These results show that bystander activation occurs during primary HIV infection, even though HIV-specific CD8(+) T cells express the highest level of activation. The role of this bystander activation in lymphocyte homeostasis and HIV pathogenesis remains to be determined.

No abstract