Immunosenescence in chronic HIV infected patients impairs essential functions of their natural killer cells

Soares, Luana Silva; Espíndola, Milena S.; Zambuzi, Fabiana Albani; Galvão-Lima, Leonardo J.; Cacemiro, Maira Costa; Soares, Murilo Racy; Santana, Bárbara Amélia Aparecida; Calado, Rodrigo T.; Bollela, Valdes Roberto; Frantz, Fabiani Gai

doi:10.1016/j.intimp.2020.106568

Cited by 10 publications

(7 citation statements)

References 30 publications

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“…While there is optimism regarding the potential of combination approaches, it is important to acknowledge that a scalable, clinically well-tolerated therapeutic strategy to either cure or control HIV in the absence of ART is unlikely to occur in the same timescale as has been proposed to end the HIV epidemic (ie, by 2030) [ 6 , 8 ]. As such, an emerging area of concern is to address how age-related perturbations in immune function and HIV-associated immunosenescence [ 162 – 164 ] intersect with the maintenance of infected cells during long-term ART [ 165 ], with the risk of co-morbidities [ 166 - 168 ], and with responsiveness to immune-based cure strategies [ 169 – 171 ]. Moreover, a portfolio of experimental and FDA-approved drugs are under investigation for their ability to either eliminate (ie, senolytics) or alter the function (ie, senomorphic) of senescent cells, including Bcl-2 inhibitors (Venetoclax), JAK1/JAK2 inhibitors (ruxolitinib), mTOR inhibitors (rapamycin), and tyrosine kinase inhibitors (dasatinib) among others [ 172 , 173 ]; however, further study is required to evaluate these agents for their utility in attenuating or reversing HIV-induced immunosenescence and affecting HIV persistence.…”

Section: Progress Towards a Curementioning

confidence: 99%

Progress Note 2024: Curing HIV; Not in My Lifetime or Just Around the Corner?

Harper,

Betts,

Lichterfeld

et al. 2024

PAI

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Once a death sentence, HIV is now considered a manageable chronic disease due to the development of antiretroviral therapy (ART) regimens with minimal toxicity and a high barrier for genetic resistance. While highly effective in arresting AIDS progression and rendering the virus untransmissible in people living with HIV (PLWH) with undetectable viremia (U=U) [1, 2]), ART alone is incapable of eradicating the “reservoir” of resting, latently infected CD4+ T cells from which virus recrudesces upon treatment cessation. As of 2022 estimates, there are 39 million PLWH, of whom 86% are aware of their status and 76% are receiving ART [3]. As of 2017, ART-treated PLWH exhibit near normalized life expectancies without adjustment for socioeconomic differences [4]. Furthermore, there is a global deceleration in the rate of new infections [3] driven by expanded access to pre-exposure prophylaxis (PrEP), HIV testing in vulnerable populations, and by ART treatment [5]. Therefore, despite outstanding issues pertaining to cost and access in developing countries, there is strong enthusiasm that aggressive testing, treatment, and effective viral suppression may be able to halt the ongoing HIV epidemic (ie, UNAIDS’ 95-95-95 targets) [6–8]; especially as evidenced by recent encouraging observations in Sydney [9]. Despite these promising efforts to limit further viral transmission, for PLWH, a “cure” remains elusive; whether it be to completely eradicate the viral reservoir (ie, cure) or to induce long-term viral remission in the absence of ART (ie, control; Figure 1). In a previous salon hosted by Pathogens and Immunity in 2016 [10], some researchers were optimistic that a cure was a feasible, scalable goal, albeit with no clear consensus on the best route. So, how are these cure strategies panning out? In this commentary, 8 years later, we will provide a brief overview on recent advances and failures towards identifying determinants of viral persistence and developing a scalable cure for HIV. Based on these observations, and as in the earlier salon, we have asked several prominent HIV cure researchers for their perspectives.

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Section: Progress Towards a Curementioning

confidence: 99%

Progress Note 2024: Curing HIV; Not in My Lifetime or Just Around the Corner?

Harper,

Betts,

Lichterfeld

et al. 2024

PAI

View full text Add to dashboard Cite

show abstract

“…However, the quantification of global DNA methylation by ELISA, has yielded inconsistent results in PLWH. Some studies have shown an increase [ 61 – 63 ] while others have reported a decrease [ 46 , 64 ] in DNA methylation in PLWH, although it is important to note that these studies used different kits for quantification, making it difficult to compare the results. It has been shown that DNA methylation differs between different immune cell types [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

Global DNA methylation and telomere length as markers of accelerated aging in people living with HIV and non-alcoholic fatty liver disease

Moreno,

Martínez-Sanz,

Martín-Mateos

et al. 2023

BMC Genomics

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Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a comorbidity that generally increases in people living with HIV (PLWH). This condition is usually accompanied by persistent inflammation and premature immune system aging. In this prospective cohort study, we describe a straightforward methodology for quantifying biomarkers of aging, such as DNA methylation and telomere length, in PLWH and in the context of another relevant condition, such as MAFLD. Fifty-seven samples in total, thirty-eight from PLWH and nineteen from non-PLWH participants with or without MAFLD, were obtained and subjected to DNA extraction from peripheral blood mononuclear cells (PBMCs). Global DNA methylation and telomere length quantification were performed using an adapted enzyme-linked immunosorbent assay (ELISA) and qPCR, respectively. The quantification results were analysed and corrected by clinically relevant variables in this context, such as age, sex, and metabolic syndrome. Our results show an increased association of these biomarkers in PLWH regardless of their MAFLD status. Thus, we propose including the quantification of these age-related factors in studies of comorbidities. This will allow a better understanding of the effect of comorbidities of HIV infection and MAFLD and prevent their effects in these populations in the future.

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“…Reactive oxygen species (ROS) and telomere length are key factors in determining cellular longevity ( 31 , 32 ), and Soares et al. reported that NK cells produce increased levels of ROS and exhibit shortened telomere length in individuals with chronic HIV infection ( 33 ). In addition, Campos et al.…”

Section: Nk Cell Dysfunction During Hiv Infectionmentioning

confidence: 99%

“…Desdıń-Micóet al recently confirmed that inflammation induces distal tissue senescence in Tfam fl/fl Cd4 Cre mice (30). Reactive oxygen species (ROS) and telomere length are key factors in determining cellular longevity (31,32), and Soares et al reported that NK cells produce increased levels of ROS and exhibit shortened telomere length in individuals with chronic HIV infection (33). In addition, Campos et al reported an increased percentage of CD56 neg CD16 pos NK cells in healthy elderly individuals and lower levels of Granzyme expression compared with healthy young individuals (4).…”

Section: Inflammatory Environment Accelerates Nk Cell Senescencementioning

confidence: 99%

Negative Regulation and Protective Function of Natural Killer Cells in HIV Infection: Two Sides of a Coin

2022

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Natural killer (NK) cells play an important immunologic role, targeting tumors and virus-infected cells; however, NK cells do not impede the progression of human immunodeficiency virus (HIV) infection. In HIV infection, NK cells exhibit impaired functions and negatively regulate other immune cell responses, although NK cells can kill HIV-infected cells and thereby suppress HIV replication. Considerable recent research has emerged regarding NK cells in the areas of immune checkpoints, negative regulation, antibody-dependent cell-mediated cytotoxicity and HIV reservoirs during HIV infection; however, no overall summary of these factors is available. This review focuses on several important aspects of NK cells in relation to HIV infection, including changes in NK cell count, subpopulations, and immune checkpoints, as well as abnormalities in NK cell functions and NK cell negative regulation. The protective function of NK cells in inhibiting HIV replication to reduce the viral reservoir and approaches for enhancing NK cell functions are also summarized.

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Immunosenescence in chronic HIV infected patients impairs essential functions of their natural killer cells

Cited by 10 publications

References 30 publications

Progress Note 2024: Curing HIV; Not in My Lifetime or Just Around the Corner?

Progress Note 2024: Curing HIV; Not in My Lifetime or Just Around the Corner?

Global DNA methylation and telomere length as markers of accelerated aging in people living with HIV and non-alcoholic fatty liver disease

Negative Regulation and Protective Function of Natural Killer Cells in HIV Infection: Two Sides of a Coin

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