Defective Human Immunodeficiency Virus-Specific CD8 ⁺ T-Cell Polyfunctionality, Proliferation, and Cytotoxicity Are Not Restored by Antiretroviral Therapy

Abstract

Identifying the functions of human immunodeficiency virus (HIV)-specific CD8؉ T cells that are not merely modulated by the level of virus but clearly distinguish patients with immune control from those without such control is of paramount importance. Features of the HIV-specific CD8؉ T-cell response in antiretroviraltreated patients (designated Rx <50) and untreated patients (long-term nonprogressors [LTNP]) matched for very low HIV RNA levels were comprehensively examined. The proliferative capacity of HIV-specific CD8 ؉ T cells was not restored in Rx <50 to the level observed in LTNP, even though HIV-specific CD4؉ T-cell proliferation in the two patient groups was comparable. This diminished HIV-specific CD8؉ T-cell proliferation in Rx <50 was primarily due to a smaller fraction of antigen-specific cells recruited to divide and not to the numbers of divisions that proliferating cells had undergone. Exogenous interleukin-2 (IL-2) induced proliferating cells to divide further but did not rescue the majority of antigen-specific cells with defective proliferation. In addition, differences in HIV-specific CD8؉ T-cell proliferation could not be attributed to differences in cellular subsets bearing a memory phenotype, IL-2 production, or PD-1 expression. Although polyfunctionality of HIV-specific CD8 ؉ T cells in Rx <50 was not restored to the levels observed in LTNP despite prolonged suppression of HIV RNA levels, per-cell cytotoxic capacity was the functional feature that most clearly distinguished the cells of LTNP from those of Rx <50. Taken together, these data suggest that there are selective qualitative abnormalities within the HIV-specific CD8 ؉ T-cell compartment that persist under conditions of low levels of antigen.

Sprouty-2 regulates HIV-specific T cell polyfunctionality

“…As compared with acute infection such as influenza, HIV-specific CTL responses in infected patients are known to have significantly lower levels of polyfunctionality, and CTL dysfunction is not restored by antiretroviral therapy (9,35). Recent studies indicate that inhibition of the PD-1 pathway partially reverses low polyfunctionality associated with chronic viral infection (13).…”

Lymphocytic Alveolitis Is Associated with the Accumulation of Functionally Impaired HIV-Specific T Cells in the Lung of Antiretroviral Therapy–Naive Subjects

“…HIV-1-specific T cells in the blood are functionally impaired during chronic HIV-1 infection (21)(22)(23)36), which is in part caused by exhaustion and overexpression of inhibitory receptors (11)(12)(13). These exhausted T cells lose effector functions and exhibit antigen-independent homeostatic proliferation (37).…”

Comparative Analysis of the Capacity of Elite Suppressor CD4 + and CD8 + T Cells To Inhibit HIV-1 Replication in Monocyte-Derived Macrophages

“…Many studies have shown that CD8 ϩ T cells from ESs are more effective at inhibiting viral replication in CD4 ϩ T cells than CD8 ϩ T cells from chronic progressors (CPs) (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Furthermore, HIV-1-specific CD4 ϩ T cells from ESs have high-avidity T cell receptors and are more likely to maintain responses that are either proliferative, polyfunctional, or cytotoxic than effector CD4 ϩ T cells from CPs (12)(13)(14)(15)(16)(17)(18)(19).…”