CD4+ T cells with an activated and exhausted phenotype distinguish immunodeficiency during aviremic HIV-2 infection

Abstract

Objective:HIV type 2 (HIV-2) represents an attenuated form of HIV, in which many infected individuals remain ‘aviremic’ without antiretroviral therapy. However, aviremic HIV-2 disease progression exists, and in the current study, we therefore aimed to examine if specific pathological characteristics of CD4+ T cells are linked to such outcome.Design:HIV-seronegative (n = 25), HIV type 1 (HIV-1) (n = 33), HIV-2 (n = 39, of whom 26 were aviremic), and HIV-1/2 dually (HIV-D) (n = 13)-infected study participants were enrolled from an occupational cohort in Guinea-Bissau.Methods:CD4+ T-cell differentiation, activation, exhaustion, senescence, and transcription factors were assessed by polychromatic flow cytometry. Multidimensional clustering bioinformatic tools were used to identify CD4+ T-cell subpopulations linked to infection type and disease stage.Results:HIV-2-infected individuals had early and late-differentiated CD4+ T-cell clusters with lower activation (CD38+HLA-DR+) and exhaustion programmed death-1 (PD-1) than HIV-1 and HIV-D-infected individuals. We also noted that aviremic HIV-2-infected individuals possessed fewer individuals. CD4+ T cells with pathological signs compared to other HIV-infected groups. Still, compared to HIV-seronegative individuals, aviremic HIV-2-infected individuals had T-bet+ CD4+ T cells that showed elevated immune activation/exhaustion, and particularly the frequencies of PD-1+ cells were associated with a suboptimal percentage of CD4+ T cells.Conclusion:Increased frequencies of CD4+ T cells with an activated/exhausted phenotype correlate with exacerbated immunodeficiency in aviremic HIV-2-infected individuals. Thus, these findings encourage studies on the introduction of antiretroviral therapy also to individuals with aviremic HIV-2 infection.

Human Immunodeficiency Virus Type-1 Elite Controllers Maintain Low Co-Expression of Inhibitory Receptors on CD4+ T Cells

“…Despite CD4+ T cells are critical for control of viral infections, less is known about their co-expression pattern of inhibitory receptor in HIV-1 infection and in relation to healthy subjects. Our preliminary studies showed negligible expression of Tim-3, LAG-3, and CD160 on CD4+ T cells and a strong association of 2B4 and KLRG-1 with effector CD4+ T cells (data not shown), similar to as described in other studies ( 15 , 21 , 29 , 30 ). We therefore focused on assessing the expression pattern of PD-1, CTLA-4, and TIGIT on different CD4+ memory T cell populations, defined by surface markers CD27, CD45RO, and CCR7, using multiparametric flow cytometry.…”

“…Recent studies in mice have demonstrated a relationship between the transcription factors FoxP3 and Ikzf2 (Helios), and an exhausted state for CD4+ T cells in chronic LCMV infection ( 20 ), findings that could be of translational importance in HIV-1 disease. In the setting of HIV-1, studies have shown that HIV-infected subjects harbor increased levels of CD4+ T cells expressing PD-1, Lag-3, CTLA-4, and 2B4, among others ( 11 , 12 , 21 – 23 ). Furthermore, several studies on ELCs have shown that natural control of HIV-1 is associated with more vigorous and polyfunctional responses of HIV-specific CD4+ T cells ( 24 , 25 ).…”

Sugar or Fat?—Metabolic Requirements for Immunity to Viral Infections

“…Acute HIV infection is associated with high levels of CD4 + and CD8 + T cell activation and exhaustion, which is often maintained throughout chronic infection due to prolonged exposure to antigenic and inflammatory signals even in anti-retroviral-treated individuals ( 74 , 75 ). Markers of T cell activation, such as CD38 and HLADR, remain elevated above normal in HIV positive individuals with durable viral suppression on ART ( 76 ). Moreover, elevated expression of co-inhibitory receptors, such as PD-1, TIGIT, CD160, and 2B4, is associated with functionally exhausted HIV-specific and non-specific CD8 + T cells with reduced proliferative capacity and impaired effector functions ( 77 – 80 ).…”

Low Levels of T Cell Exhaustion in Tuberculous Lung Granulomas

“…This subpopulation of T cells enters an "exhausted" state, characterized by low cytokine production, low proliferation, and expression of a series of inhibitory receptors. The most well studied of these receptors include PD-1, CTLA-4, and LAG-3, which interact with a range of ligands to activate negative regulatory pathways (13,14). While these inhibitory receptors may balance an overly activated immune response that could lead to disease pathology, the receptors can also prevent an effective immune response from clearing infections and tumor cells.…”

“…Confounding these data, the relationship between inhibitory markers and functional exhaustion is not abundantly clear. Recent studies have shown that inhibitory receptors can act as activation markers and that T cells can simultaneously express both inhibitory and activation markers (14,(32)(33)(34)(35). Therefore, it becomes difficult to distinguish T cell exhaustion using inhibitory receptors alone.…”