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Persistence of Activated and Adaptive-Like NK Cells in HIV⁺ Individuals despite 2 Years of Suppressive Combination Antiretroviral Therapy.

ABSTRACT: Innate immune dysfunction persists in HIV⁺ individuals despite effective combination antiretroviral therapy (cART). We recently demonstrated that an adaptive-like CD56^dim NK cell population lacking the signal transducing protein FcR? is expanded in HIV⁺ individuals. Here, we analyzed a cohort of HIV⁺ men who have sex with men (MSM, n?=?20) at baseline and following 6, 12, and 24?months of cART and compared them with uninfected MSM (n?=?15) to investigate the impact of cART on NK cell dysfunction. Proportions of NK cells expressing markers of early (CD69⁺) and late (HLA-DR⁺/CD38⁺) activation were elevated in cART-naïve HIV⁺ MSM (p?=?0.004 and 0.015, respectively), as were FcR?^- NK cells (p?=?0.003). Using latent growth curve modeling, we show that cART did not reduce levels of FcR?^- NK cells (p?=?0.115) or activated HLA-DR⁺/CD38⁺ NK cells (p?=?0.129) but did reduce T cell and monocyte activation (p?- NK cells were not associated with NK cell, T cell, or monocyte activation, suggesting different factors drive CD56^dim FcR?^- NK cell expansion and immune activation in HIV⁺ individuals. While proportions of activated CD69⁺ NK cells declined significantly on cART (p?=?0.003), the rate was significantly slower than the decline of T cell and monocyte activation, indicating a reduced potency of cART against NK cell activation. Our findings indicate that 2?years of suppressive cART have no impact on CD56^dim FcR?^- NK cell expansion and that NK cell activation persists after normalization of other immune parameters. This may have implications for the development of malignancies and co-morbidities in HIV⁺ individuals on cART.

SUBMITTER: Hearps AC

PROVIDER: S-EPMC5491541 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Persistence of Activated and Adaptive-Like NK Cells in HIV+ Individuals despite 2 Years of Suppressive Combination Antiretroviral Therapy.

Hearps Anna C AC Agius Paul A PA Zhou Jingling J Brunt Samantha S Chachage Mkunde M Angelovich Thomas A TA Cameron Paul U PU Giles Michelle M Price Patricia P Elliott Julian J Jaworowski Anthony A

Frontiers in immunology 20170630

Innate immune dysfunction persists in HIV+ individuals despite effective combination antiretroviral therapy (cART). We recently demonstrated that an adaptive-like CD56dim NK cell population lacking the signal transducing protein FcRγ is expanded in HIV+ individuals. Here, we analyzed a cohort of HIV+ men who have sex with men (MSM, n = 20) at baseline and following 6, 12, and 24 months of cART and compared them with uninfected MSM (n = 15 ...[more]

PMID: 28713370

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Project description:The quantification of proviral DNA is raising interest in view of clinical management and functional HIV eradication. Measures of all unintegrated HIV DNA (uDNA) forms in infected reservoir cells provides information on recent replication events that is not found from other proviral DNA assays. To evaluate its actual relevance in a cohort of perinatally-infected adult HIV patients (PHIV), we studied how peripheral blood mononuclear cell uDNA levels correlated with total HIV DNA (tDNA) and with overall replication or innate immune control parameters including NK cell activation/exhaustion and lymphoid turnover. Twenty-two PHIV were included, with successfully controlled HIV (HIV RNA <50 copies/mL) on combined antiretroviral therapy for mean of 8.7 ± 3.9 years. uDNA accounted for 16 [5.2-83.5] copies/µg and was strongly correlated with tDNA (ρ=0.700, p=0.001). Flow cytometric analysis of peripheral NK cells showed that CD69 expression was directly correlated uDNA (p=0.0412), but not with tDNA. Interestingly, CD56-CD16+NK cells which include newly described inflammatory precursors and terminally differentiated cells were directly correlated with uDNA levels (p<0.001), but not with tDNA, and an inverse association was observed between the proportion of NKG2D+ NK cells and uDNA (ρ=-0.548, p=0.015). In addition, CD34+DNAM-1brightCXCR4+ inflammatory precursor frequency correlated directly with uDNA levels (ρ=0.579, p=0.0075). The frequencies of CD56-CD16+ and CD34+DNAM-1brightCXCR4+ cells maintained association with uDNA levels in a multivariable analysis (p=0.045 and p=0.168, respectively). Thus, control of HIV-1 reservoir in aviremic patients on ART is an active process associated with continuous NK cell intervention and turnover, even after many years of treatment. Quantification of linear and circular uDNA provides relevant information on the requirement for ongoing innate immune control in addition to ART, on recent replication history and may help stratify patients for functional HIV eradication protocols with targeted options.

Project description:Current shock-and-kill strategies for the eradication of the HIV-1 reservoir have resulted in blips of viremia but not in a decrease in the size of the latent reservoir in patients on suppressive antiretroviral therapy (ART). This discrepancy could potentially be explained by an inability of the immune system to kill HIV-1-infected cells following the reversal of latency. Furthermore, some studies have suggested that certain latency-reversing agents (LRAs) may inhibit CD8+ T cell and natural killer (NK) cell responses. In this study, we tested the hypothesis that alpha interferon (IFN-?) could improve the function of NK cells from chronic progressors (CP) on ART. We show here that IFN-? treatment enhanced cytokine secretion, polyfunctionality, degranulation, and the cytotoxic potential of NK cells from healthy donors (HD) and CP. We also show that this cytokine enhanced the viral suppressive capacity of NK cells from HD and elite controllers or suppressors. Furthermore, IFN-? enhanced global CP CD8+ T cell cytokine responses and the suppressive capacity of ES CD8+ T cells. Our data suggest that IFN-? treatment may potentially be used as an immunomodulatory agent in HIV-1 cure strategies.IMPORTANCE Data suggest that HIV+ individuals unable to control infection fail to do so due to impaired cytokine production and/cytotoxic effector cell function. Consequently, the success of cure agendas such as the shock-and-kill strategy will probably depend on enhancing patient effector cell function. In this regard, NK cells are of particular interest since they complement the function of CD8+ T cells. Here, we demonstrate the ability of short-course alpha interferon (IFN-?) treatments to effectively enhance such effector functions in chronic progressor NK cells without inhibiting their general CD8+ T cell function. These results point to the possibility of exploring such short-course IFN-? treatments for the enhancement of effector cell function in HIV+ patients in future cure strategies.

Dataset Information

Persistence of Activated and Adaptive-Like NK Cells in HIV⁺ Individuals despite 2 Years of Suppressive Combination Antiretroviral Therapy.

Publications

Persistence of Activated and Adaptive-Like NK Cells in HIV<sup>+</sup> Individuals despite 2 Years of Suppressive Combination Antiretroviral Therapy.

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