Sustained Impairment of IFN-γ Secretion in Suppressed HIV-Infected Patients Despite Mature NK Cell Recovery: Evidence for a Defective Reconstitution of Innate Immunity

Abstract

The impairment of NK cell functions in the course of HIV infection contributes to a decreased resistance against HIV and other pathogens. We analyzed the proportion of mature and immature NK cell subsets, and measured subsets of IFN-γ and TNF-α-producing NK and T cells in viremic or therapy-suppressed HIV-infected subjects, and noninfected control donors. Viremic HIV+ individuals had significantly lower proportions of mature CD3−/CD161+/CD56+ NK cells and of IFN-γ-producing NK cells compared with noninfected donors, independent of CD4+ T cell counts. HIV-infected subjects with undetectable viral load recovered mature CD3−/CD161+/CD56+ NK cells and cytotoxicity against tumor (K562) and HSV-infected target cells to percentages comparable with those of uninfected individuals, but their NK cells remained impaired in their ability to produce IFN-γ. In parallel to these ex vivo findings, in vitro NK cell differentiation of CD34-positive cord blood precursors in the presence of R5 or X4 HIV-1 resulted in the production of NK cells with a normal mature phenotype, but lacking the ability to produce IFN-γ, whereas coculture of uninfected PBMC with HIV failed to affect mature NK cell properties or IFN-γ secretion. Altogether, our findings support the hypothesis that mature NK cell phenotype may be uncoupled from some mature functions following highly active antiretroviral therapy-mediated suppression of HIV-1, and indicate that relevant innate immune functions of NK cell subsets may remain altered despite effective viral suppression following antiretroviral treatment.

Differential Effects of Interleukin-7 and Interleukin-15 on NK Cell Anti-Human Immunodeficiency Virus Activity

“…A significantly lower proportion of CD3 Ϫ CD16 ϩ CD56 ϩ NK cells are found in HIV-infected patients with uncontrolled HIV replication (6), in comparison to patients with therapeutically suppressed HIV viremia. Moreover, NK cell activity is impaired by both a reduction of NK cell number and a reduction in NK cell cytolytic function (27,44,69).…”

Single-Stranded RNA Derived from HIV-1 Serves as a Potent Activator of NK Cells

“…The perturbations observed in the NK cell compartment during chronic HIV-1 infection include the overall increased activation of NK cells, the early loss of CD3 Ϫ CD56 bright NK cells, the accumulation of anergic CD3 Ϫ CD56 Ϫ CD16 ϩ NK cells (6,10), and the impairment of their cytotoxic capacity (6,9,10,56) and cross-talk with DCs (11). The mechanisms underlying these numeric and functional NK cell perturbations observed during viremic HIV-1 infection are not understood.…”

“…The mechanisms underlying these numeric and functional NK cell perturbations observed during viremic HIV-1 infection are not understood. However, suppression of HIV-1 viremia by antiretroviral therapy results in at least a partial reconstitution of NK cell numbers and function (6,9,55). Recently, it has been demonstrated that ssRNA derived from HIV-1 LTR can activate DCs via TLR7/8 (2,25).…”

“…Chronic viremic HIV-1 infection is characterized by persistent immune activation (30) and the functional impairment of several lymphocyte populations (50 -52), including NK cells (9,10,12,(53)(54)(55). The perturbations observed in the NK cell compartment during chronic HIV-1 infection include the overall increased activation of NK cells, the early loss of CD3 Ϫ CD56 bright NK cells, the accumulation of anergic CD3 Ϫ CD56 Ϫ CD16 ϩ NK cells (6,10), and the impairment of their cytotoxic capacity (6,9,10,56) and cross-talk with DCs (11).…”

Selective Serotonin Reuptake Inhibitor and Substance P Antagonist Enhancement of Natural Killer Cell Innate Immunity in Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome

“…Numerous experimental and clinical studies have documented this finding (6)(7)(8). The negative effects of HIV on NK cells are pervasive, involving both the quantity and functions of NK cells.…”