Progressive loss of T cell functionality is a hallmark of chronic infection with human immunodeficiency virus 1 (HIV-1). We have identified a novel population of dysfunctional T cells marked by surface expression of the glycoprotein Tim-3. The frequency of this population was increased in HIV-1–infected individuals to a mean of 49.4 ± SD 12.9% of CD8⁺ T cells expressing Tim-3 in HIV-1–infected chronic progressors versus 28.5 ± 6.8% in HIV-1–uninfected individuals. Levels of Tim-3 expression on T cells from HIV-1–infected inviduals correlated positively with HIV-1 viral load and CD38 expression and inversely with CD4⁺ T cell count. In progressive HIV-1 infection, Tim-3 expression was up-regulated on HIV-1–specific CD8⁺ T cells. Tim-3–expressing T cells failed to produce cytokine or proliferate in response to antigen and exhibited impaired Stat5, Erk1/2, and p38 signaling. Blocking the Tim-3 signaling pathway restored proliferation and enhanced cytokine production in HIV-1–specific T cells. Thus, Tim-3 represents a novel target for the therapeutic reversal of HIV-1–associated T cell dysfunction.

Twenty-one consecutive patients with streptococcal toxic shock syndrome (TSS) between December 1994 and April 1995 were treated with a median dose of

Many immune correlates of CD8⁺ T-cell-mediated control of HIV replication, including polyfunctionality, proliferative ability, and inhibitory receptor expression, have been discovered. However, no functional correlates using ex vivo cells have been identified with the known ability to cause the direct elimination of HIV-infected cells. We have recently discovered the ability of human CD8⁺ T-cells to rapidly upregulate perforin—an essential molecule for cell-mediated cytotoxicity—following antigen-specific stimulation. Here, we examined perforin expression capability in a large cross-sectional cohort of chronically HIV-infected individuals with varying levels of viral load: elite controllers (n = 35), viremic controllers (n = 29), chronic progressors (n = 27), and viremic nonprogressors (n = 6). Using polychromatic flow cytometry and standard intracellular cytokine staining assays, we measured perforin upregulation, cytokine production, and degranulation following stimulation with overlapping peptide pools encompassing all proteins of HIV. We observed that HIV-specific CD8⁺ T-cells from elite controllers consistently display an enhanced ability to express perforin directly ex vivo compared to all other groups. This ability is not restricted to protective HLA-B haplotypes, does not require proliferation or the addition of exogenous factors, is not restored by HAART, and primarily originates from effector CD8⁺ T-cells with otherwise limited functional capability. Notably, we found an inverse relationship between HIV-specific perforin expression and viral load. Thus, the capability of HIV-specific CD8⁺ T-cells to rapidly express perforin defines a novel correlate of control in HIV infection. While the majority HIV-infected individuals progress to AIDS, a fraction of these individuals—for reasons not completely understood—do not develop AIDS and also display sustained control over viral replication; these subjects are sometimes referred to as elite controllers (EC). Prior evidence has shown that HIV-specific CD8⁺ T-cells, a component of adaptive immunity against intracellular pathogens, from EC exhibit enhanced functionality compared to individuals with progressive disease. Therefore, HIV-specific CD8⁺ T-cells likely play an important role in the favorable clinical outcomes witnessed in EC. We show in this study that the ability to control HIV replication in EC is associated with the expression of a protein called perforin, a critical molecule that enables CD8⁺ T-cells to directly kill infected cells - thereby preventing the spread of HIV to previously uninfected cells. In infected subjects with nonprogressive disease, we show that HIV-specific CD8⁺ T-cells demonstrate a superior ability to express perforin upon antigen-specific stimulation, whereas in progressors this property is diminished. Thus, we identify a functional capability of CD8⁺ T-cells, readily measured by standard intracellular cytokine staining assays, that potentially has a direct impact on HIV replication in vivo. These findings may, therefore, provide an important qualifier for future HIV vaccine research.

Both activated and resting CD4 ⁺ T cells in mucosal tissues play important roles in the earliest phases of infection after sexual transmission of HIV-1, a process that is inefficient. HIV-1 gp120 binds to integrin α ₄ β ₇ (α ₄ β ₇ ), the gut mucosal homing receptor. We find that α ₄ β ₇ ^high CD4 ⁺ T cells are more susceptible to productive infection than are α ₄ β ₇ ^low-neg CD4 ⁺ T cells in part because this cellular subset is enriched with metabolically active CD4 ⁺ T cells. α ₄ β ₇ ^high CD4 ⁺ T cells are CCR5 ^high and CXCR4 ^low ; on these cells, α ₄ β ₇ appears in a complex with CD4. The specific affinity of gp120 for α ₄ β ₇ provides a mechanism for HIV-1 to target activated cells that are critical for efficient virus propagation and dissemination following sexual transmission.

Bacterial vaginosis (BV) is a common yet poorly understood vaginal condition that has become a major focus of HIV transmission and immunology research. Varied terminologies are used by clinicians and researchers to describe microbial communities that reside in the female reproductive tract (FRT), which is driven, in part, by microbial genetic and metabolic complexity, evolving diagnostic and molecular techniques, and multidisciplinary perspectives of clinicians, epidemiologists, microbiologists, and immunologists who all appreciate the scientific importance of understanding mechanisms that underlie BV. This Perspectives article aims to clarify the varied terms used to describe the cervicovaginal microbiota and its “nonoptimal” state, under the overarching term of BV. The ultimate goal is to move toward language standardization in future literature that facilitates a better understanding of the impact of BV on FRT immunology and risk of sexually transmitted infections, including HIV.