Epigenetic Age Acceleration Markers Are Associated With Physiologic Frailty and All-Cause Mortality in People With Human Immunodeficiency Virus.

BACKGROUND: Biomarkers that provide insight into drivers of aging are needed for people with human immunodeficiency virus (PWH). The study objective was to determine if epigenetic age acceleration (EAA) markers are associated with physiologic frailty measured by the Veterans Aging Cohort Study (VACS) Index and predict all-cause mortality for PWH. METHODS: Epigenome-wide DNA methylation was profiled in VACS total white blood cell samples collected during 2005-2007 from 531 PWH to generate 6 established markers of EAA. The association of each EAA marker was tested with VACS Index 2.0. All-cause mortality was assessed over 10 years. For each EAA marker, the hazard ratio per increased year was determined using Cox regression. To evaluate mortality discrimination, C-statistics were derived. RESULTS: Participants were mostly men (98.5%) and non-Hispanic Black (84.4%), with a mean age of 52.4 years (standard deviation [SD], 7.8 years). Mean VACS Index score was 59.3 (SD, 16.4) and 136 deaths occurred over a median follow-up of 8.7 years. Grim age acceleration (AA), PhenoAA, HannumAA, and extrinsic epigenetic AA were associated with the VACS Index and mortality. HorvathAA and intrinsic epigenetic AA were not associated with either outcome. GrimAA had the greatest mortality discrimination among EAA markers and predicted mortality independently of the VACS Index. One-year increase in GrimAA was associated with a 1-point increase in VACS Index and a 10% increased hazard for mortality. CONCLUSIONS: The observed associations between EAA markers with physiologic frailty and mortality support future research to provide mechanistic insight into the accelerated aging process and inform interventions tailored to PWH for promoting increased healthspan.

Testosterone supplementation upregulates androgen receptor expression and translational capacity during severe energy deficit.

Testosterone supplementation during energy deficit promotes whole body lean mass accretion, but the mechanisms underlying that effect remain unclear. To elucidate those mechanisms, skeletal muscle molecular adaptations were assessed from muscle biopsies collected before, 1 h, and 6 h after exercise and a mixed meal (40 g protein, 1 h postexercise) following 14 days of weight maintenance (WM) and 28 days of an exercise- and diet-induced 55% energy deficit (ED) in 50 physically active nonobese men treated with 200 mg testosterone enanthate/wk (TEST) or placebo (PLA) during the ED. Participants (n = 10/group) exhibiting substantial increases in leg lean mass and total testosterone (TEST) were compared with those exhibiting decreases in both of these measures (PLA). Resting androgen receptor (AR) protein content was higher and fibroblast growth factor-inducible 14 (Fn14), IL-6 receptor (IL-6R), and muscle ring-finger protein-1 gene expression was lower in TEST vs. PLA during ED relative to WM (P < 0.05). Changes in inflammatory, myogenic, and proteolytic gene expression did not differ between groups after exercise and recovery feeding. Mechanistic target of rapamycin signaling (i.e., translational efficiency) was also similar between groups at rest and after exercise and the mixed meal. Muscle total RNA content (i.e., translational capacity) increased more during ED in TEST than PLA (P < 0.05). These findings indicate that attenuated proteolysis at rest, possibly downstream of AR, Fn14, and IL-6R signaling, and increased translational capacity, not efficiency, may drive lean mass accretion with testosterone administration during energy deficit.

Atypical Skeletal Muscle Profiles in Human Immunodeficiency Virus-Infected Asymptomatic Middle-Aged Adults.

Background: Human immunodeficiency virus (HIV)-infected individuals are at increased risk of age-associated functional impairment, even with effective antiretroviral therapy (ART). A concurrent characterization of skeletal muscle, physical function, and immune phenotype in aviremic middle-aged HIV-infected adults represents a knowledge gap in prognostic biomarker discovery. Methods: We undertook a prospective observational study of 170 middle-aged, HIV-infected ambulatory men and women with CD4+ T-cell counts of at least 350/µL and undetectable plasma viremia while on effective ART, and uninfected control participants. We measured biomarkers for inflammation and immune activation, fatigue, the Veterans Aging Cohort Study mortality index, and physical function. A subset also received a skeletal muscle biopsy and computed tomography scan. Results: Compared to the uninfected participants, HIV-infected participants displayed increased immune activation (P < .001), inflammation (P = .001), and fatigue (P = .010), and in a regression model adjusting for age and sex displayed deficits in stair-climb power (P < .001), gait speed (P = .036), and predicted metabolic equivalents (P = .019). Skeletal muscle displayed reduced nuclear peroxisome proliferator-activated receptor-γ coactivator 1α-positive myonuclei (P = .006), and increased internalized myonuclei (P < .001) that correlated with immune activation (P = .003) and leukocyte infiltration (P < .001). Internalized myonuclei improved a model for HIV discrimination, increasing the C-statistic from 0.84 to 0.90. Conclusions: Asymptomatic HIV-infected middle-aged adults display atypical skeletal muscle profiles, subclinical deficits in physical function, and persistent inflammation and immune activation. Identifying biomarker profiles for muscle dysregulation and risk for future functional decline in the HIV-infected population will be key to developing and monitoring preventive interventions. Clinical Trials Registration: NCT03011957.

Enabling translational geroscience by broadening the scope of geriatric care.

Geroscience poses that core biological mechanisms of aging contribute to chronic diseases and disabilities in late life and that health span and longevity can be modulated by pharmacological and behavioral interventions. Despite strong evidence from studies in model organisms and great potentials for translation, most geriatricians remain skeptical that geroscience will help them in the day-by-day battle with the consequences of aging in their patients. We believe that a closer collaboration between gerontologists and geriatricians is the key to overcome this impasse. There is evidence that trajectories of health with aging are rooted in intrinsic and extrinsic exposures that occur early in life and affect the pace of molecular and cellular damage accumulation with aging, also referred to as the "pace" of biological aging. Tools that measure the pace of aging currently allow for the identification of individuals experiencing accelerated aging and at higher risk of multimorbidity and disability. What we term "Translational Geroscience", i.e., the merger of fundamental and translational science with clinical practice, is thus poised to extend the action of geriatric care to a life course perspective. By targeting core mechanisms of aging, gerotherapeutics should be effective in treating patients with multimorbidity and disability, phenotypes that are all too common among geriatric patients nowadays. We call for initiatives that enhance the flow of ideas between gerontologists and geriatricians to facilitate the growth of translational geroscience. This approach can widen the scope of geriatric care, including a new role for geroscience in the promotion and operationalization of healthy longevity.

Healthy aging: Linking causal mechanisms with holistic outcomes.

Identifying and understanding the impact of differing exposures over the lifecourse necessitates contextualizing different levels of influence ranging from genetics, epigenetics, geography, and psychosocial networks.

Poor sleep quality is linked to increased frailty in middle-aged people living with HIV in Botswana.

This work aims to evaluate associations between self-reported sleep health and frailty in Botswana, a sub-Saharan Africa setting. Fifty persons living with HIV (PLWH) on suppressive antiretroviral therapy (ART) and fifty HIV seronegative control participants are enrolled in Botswana. Sleep quality is scored subjectively as "good" or "poor" based on self-report. A frailty index (FI) is constructed based on thirty-three health deficits related to body mass index, waist circumference, physical activity, emotional status, and fatigue, and scored ranging between 0 (no deficit present) and 1 (all deficits present). Sleep quality between PLWH and controls is compared using logistic regression; linear regression is performed to compare the FI between them. Linear regressions are performed to examine the association between the FI and sleep quality stratified by HIV serostatus. Age, sex, and comorbidities are adjusted; when relevant, CD4 cell and ART duration are controlled. PLWH display 2.88 (95% CI: 1.22-6.79, p = 0.02) higher odds of having poor sleep than controls. Having poor sleep is associated with increased FI in PLWH but not in controls. Specifically, compared with PLWH who have good sleep, PLWH who report poor sleep have a > 1 standard deviation (p < 0.0001) increase in their FI score.

Maladaptive Immune Activation in Age-Related Decline of Muscle Function.

Age-related changes in immune competency and inflammation play a role in the decline of physical function. In this review of the conference on Function-Promoting Therapies held in March 2022, we discuss the biology of aging and geroscience with an emphasis on decline in physical function and the role of age-related changes in immune competence and inflammation. More recent studies in skeletal muscle and aging highlighting a crosstalk between skeletal muscle, neuromuscular feedback, and immune cell subsets are also discussed. The value of strategies targeting specific pathways that affect skeletal muscle and more systems-wide approaches that provide benefits in muscle homeostasis with aging are underscored. Goals in clinical trial design and the need for incorporating differences in life history when interpreting results from these intervention strategies are important. Where applicable, references are made to papers presented at the conference. We conclude by underscoring the need to incorporate age-related immune competency and inflammation when interpreting results from interventions that target specific pathways predicted to promote skeletal muscle function and tissue homeostasis.

Can statin preventative treatment inform geroscience-guided therapeutics?

Potential senotherapeutic effect of statins may lead to prevention and reduction of frailty.

Multi-modal profiling of peripheral blood cells across the human lifespan reveals distinct immune cell signatures of aging and longevity.

BACKGROUND: Age-related changes in immune cell composition and functionality are associated with multimorbidity and mortality. However, many centenarians delay the onset of aging-related disease suggesting the presence of elite immunity that remains highly functional at extreme old age. METHODS: To identify immune-specific patterns of aging and extreme human longevity, we analyzed novel single cell profiles from the peripheral blood mononuclear cells (PBMCs) of a random sample of 7 centenarians (mean age 106) and publicly available single cell RNA-sequencing (scRNA-seq) datasets that included an additional 7 centenarians as well as 52 people at younger ages (20-89 years). FINDINGS: The analysis confirmed known shifts in the ratio of lymphocytes to myeloid cells, and noncytotoxic to cytotoxic cell distributions with aging, but also identified significant shifts from CD4+ T cell to B cell populations in centenarians suggesting a history of exposure to natural and environmental immunogens. We validated several of these findings using flow cytometry analysis of the same samples. Our transcriptional analysis identified cell type signatures specific to exceptional longevity that included genes with age-related changes (e.g., increased expression of STK17A, a gene known to be involved in DNA damage response) as well as genes expressed uniquely in centenarians' PBMCs (e.g., S100A4, part of the S100 protein family studied in age-related disease and connected to longevity and metabolic regulation). INTERPRETATION: Collectively, these data suggest that centenarians harbor unique, highly functional immune systems that have successfully adapted to a history of insults allowing for the achievement of exceptional longevity. FUNDING: TK, SM, PS, GM, SA, TP are supported by NIH-NIAUH2AG064704 and U19AG023122. MM and PS are supported by NIHNIA Pepper center: P30 AG031679-10. This project is supported by the Flow Cytometry Core Facility at BUSM. FCCF is funded by the NIH Instrumentation grant: S10 OD021587.

Sca-1 is negatively regulated by TGF-beta1 in myogenic cells.

Sca-1 (stem cell antigen-1) is a member of the Ly-6 family of proteins and regulates cell proliferation, differentiation, and self-renewal in multiple tissues. In skeletal muscle, Sca-1 inhibits both proliferation and differentiation of myogenic cells. Sca-1 expression is dynamically regulated during muscle regeneration, and mice lacking Sca-1 display increased fibrosis following muscle injury. Here, we show that Sca-1 expression is negatively regulated by TGF-ß1 and that this inhibition is dependent on Smad3. We demonstrate that levels of TGF-ß1 in skeletal muscle rapidly increase on injury and that the majority of this TGFß1 is produced by infiltrating macrophages. Sca-1 is expressed in multiple cell types, and we demonstrate that TGF-ß1 represses Sca-1 expression in T cells and other immune cell populations derived from the spleen, indicating that regulation by TGF-ß1 is a general feature of Sca-1 expression in multiple cell types. Elucidation of the mechanisms by which Sca-1 expression is regulated may aid in the understanding of muscle homeostasis, potentially identifying novel therapeutic targets for muscle diseases.

Biological ageing with HIV infection: evaluating the geroscience hypothesis.

Although people with HIV are living longer, as they age they remain disproportionately burdened with multimorbidity that is exacerbated in resource-poor settings. The geroscience hypothesis postulates that a discrete set of between five and ten hallmarks of biological ageing drive multimorbidity, but these processes have not been systematically examined in the context of people with HIV. We examine four major hallmarks of ageing (macromolecular damage, senescence, inflammation, and stem-cell dysfunction) as gerodrivers in the context of people with HIV. As a counterbalance, we introduce healthy ageing, physiological reserve, intrinsic capacity, and resilience as promoters of geroprotection that counteract gerodrivers. We discuss emerging geroscience-based diagnostic biomarkers and therapeutic strategies, and provide examples based on recent advances in cellular senescence, and other, non-pharmacological approaches. Finally, we present a conceptual model of biological ageing in the general population and in people with HIV that integrates gerodrivers and geroprotectors as modulators of homoeostatic reserves and organ function over the lifecourse.

Geriatric Conditions Associated with Nonadherence to Antiretroviral Therapy Among Older People with HIV: The Importance of Frailty.

Poor compliance with medications is a growing concern in geriatric care and is increasingly more relevant among people living with HIV (PLWH) as they age. Our goal was to understand geriatric conditions associated with antiretroviral therapy (ART) nonadherence in a Medicare population of older PLWH. We analyzed Medicare data from PLWH aged 50 years or older who were continuously enrolled in fee-for-service Medicare from January 1, 2014 to June 30, 2015. Prevalent geriatric conditions (dementia, depression, falls, hip fracture, sensory deficits, osteoporosis, orthostatic hypotension, urinary incontinence, frailty) were identified in January 1, 2014-December 31, 2014. ART nonadherence was defined as <80% proportion of days covered (PDC) by at least two ART medications in January 1, 2015-June 30, 2015. We examined geriatric condition association with nonadherence using lowest Akaike Information Criterion multi-variate logistic models, controlling for age, sex, race, census region, substance use, Medicaid eligibility, and polypharmacy. Of 8778 PLWH, 23% (n = 2042) had <80% PDC. The average age was 60 years (standard deviation ±8), and >70% were males. In adjusted models, age was not associated with nonadherence, frailty status was the only geriatric condition associated with nonadherence [robust: reference, prefrail odds ratio (OR): 0.97, confidence interval (95% CI) 0.86-1.10, frail OR: 1.34 95% CI 1.11-1.61], and odds of nonadherence were lower for polypharmacy [OR: 0.48 (0.43-0.54)]. Our findings suggest that patient-centered care plans aimed at improving ART adherence among older PLWH would benefit from long-term surveillance; a deeper understanding of the role of frailty and polypharmacy, even at chronologically younger ages in PLWH.

Reduced Levels of NAD in Skeletal Muscle and Increased Physiologic Frailty Are Associated With Viral Coinfection in Asymptomatic Middle-Aged Adults.

BACKGROUND: People living with HIV (PLWH) are disproportionately burdened with multimorbidity and decline in physiologic function compared with their uninfected counterparts, but biological mechanisms that differentially contribute to the decline in muscle function in PLWH compared with uninfected people remain understudied. SETTING: The study site was Brigham and Women's Hospital, Harvard Medical School, Boston, MA. METHODS: We evaluated skeletal muscle tissue for levels of total nicotinamide adenine dinucleotide (NAD), NAD+, and nicotinamide adenine dinucleotide (NADH) in middle-aged asymptomatic PLWH, coinfected with hepatitis C virus and/or cytomegalovirus and compared them with uninfected control participants. RESULTS: Of the 54 persons with muscle biopsy data, the mean age was 57 years with 33% women. Total NAD levels declined in skeletal muscle in association with HIV infection and was exacerbated by hepatitis C virus and cytomegalovirus coinfection, with lowest levels of total NAD, NAD+, and NADH among persons who were coinfected with all 3 viruses (P = 0.015, P = 0.014, and P = 0.076, respectively). Levels of total NAD, NAD+, and NADH in skeletal muscle were inversely associated with inflammation (P = 0.014, P = 0.013, and P = 0.055, respectively). Coinfections were also associated with measures of inflammation (CD4/CD8 ratio: P < 0.001 and sCD163: P < 0.001) and immune activation (CD38 and human leukocyte antigen-DR expression on CD8 T cells: P < 0.001). In addition, coinfection was associated with increased physiologic frailty based on the Veteran Aging Cohort Study 1.0 index assessment (P = 0.001). CONCLUSIONS: Further research is warranted to determine the clinical relevance of preclinical deficits in NAD metabolites in skeletal muscle in association with viral coinfection and inflammation, as well as the observed association between viral coinfection and physiologic frailty.

Daytime Sleep Behaviors and Cognitive Performance in Middle- to Older-Aged Adults Living with and without HIV Infection.

PURPOSE: We investigated whether daytime sleep behaviors (DSBs) such as frequent daytime sleepiness or napping are associated with worse cognitive performance, and whether HIV infection moderates this relationship. METHODS: Among 502,507 participants in the UK Biobank study, we identified 562 people living with HIV infection (PLWH; M age= 50.51±7.81; 25.09% female; 78.83% white) and extracted 562 uninfected controls who matched on age, sex, ethnic background, social-economic status, and comorbidities. DSB burden was assessed based on answers to two questions on DSBs. Participants who answered "sometimes" or "often/usually" to one of them were considered to have poor DSB burden, or otherwise were considered not having any. A composite cognition score was computed by averaging the available standardized individual test results from four neurocognitive tests: ie, a reaction time test for information processing speed, a pairs matching test for visual episodic memory, a fluid intelligence test for reasoning, and a prospective memory test. Mixed-effects models with adjustment for the variables used in extracting matched uninfected controls were performed to test the hypotheses. RESULTS: Having poor DSB burden was associated with a 0.15 - standard deviation (SD) decrease in cognitive performance (p = 0.006). People living with HIV infection (PLWH) also performed worse on the cognitive tasks than uninfected controls, with an effect size similar to that of having poor DSB burden (p = 0.003). HIV infection significantly modified the negative association between DSB burden and cognition (p for interaction: 0.008). Specifically, the association between DSB burden and cognition was not statistically significant in uninfected controls, whereas PLWH who reported having poor DSB burden had a 0.28 - SD decrease in cognitive performance compared to PLWH who did not. CONCLUSION: HIV infection significantly increased the adverse association between DSBs and cognitive performance. Further studies are needed to investigate the potential mechanisms that underlie this interaction effect and whether poor DSBs and worse cognitive performance are causally linked.

Categorizing Comorbid Risk for People Living With HIV: A Latent Profile Analysis.

BACKGROUND: Categorizing clinical risk amidst heterogeneous multimorbidity in older people living with HIV/AIDS (PLWH) may help prioritize and optimize health care engagements. METHODS: PLWH and their prevalent conditions in 8 health domains diagnosed before January 1, 2015 were identified using 2014-2016 Medicare claims and the Chronic Conditions Data Warehouse. Latent profile analysis identified 4 distinct clinical subgroups based on the likelihood of conditions occurring together [G1: healthy, G2: substance use (SU), G3: pulmonary (PULM), G4: cardiovascular conditions (CV)]. Restricted mean survival time regression estimated the association of each subgroup with the 365 day mean event-free days until death, first hospitalization, and nursing home admission. Zero-inflated Poisson regression estimated hospitalization frequency in 2-year follow-up. RESULTS: Of 11,196 older PLWH, 71% were male, and the average age was 61 (SD 9.2) years. Compared with healthy group, SU group had a mean of 30 [95% confidence interval: (19.0 to 40.5)], PULM group had a mean of 28 (22.1 to 34.5), and CV group had a mean of 22 (15.0 to 22.0) fewer hospitalization-free days over 1 year. Compared with healthy group (2.8 deaths/100 person-years), CV group (8.4) had a mean of 4 (3.8 to 6.8) and PULM group (7.9) had a mean of 3 (0.7 to 5.5) fewer days alive; SU group (6.0) was not different. There was no difference in restricted mean survival time for nursing home admission. Compared with healthy group, SU group had 1.42-fold [95% confidence interval: (1.32 to 1.54)], PULM group had 1.71-fold (1.61 to 1.81), and CV group had 1.28-fold (1.20 to 1.37) higher rates of hospitalization. CONCLUSION: Identifying clinically distinct subgroups with latent profile analysis may be useful to identify targets for interventions and health care optimization in older PLWH.

Effects of Testosterone on Mixed-Muscle Protein Synthesis and Proteome Dynamics During Energy Deficit.

CONTEXT: Effects of testosterone on integrated muscle protein metabolism and muscle mass during energy deficit are undetermined. OBJECTIVE: The objective was to determine the effects of testosterone on mixed-muscle protein synthesis (MPS), proteome-wide fractional synthesis rates (FSR), and skeletal muscle mass during energy deficit. DESIGN: This was a randomized, double-blind, placebo-controlled trial. SETTING: The study was conducted at Pennington Biomedical Research Center. PARTICIPANTS: Fifty healthy men. INTERVENTION: The study consisted of 14 days of weight maintenance, followed by a 28-day 55% energy deficit with 200 mg testosterone enanthate (TEST, n = 24) or placebo (PLA, n = 26) weekly, and up to 42 days of ad libitum recovery feeding. MAIN OUTCOME MEASURES: Mixed-MPS and proteome-wide FSR before (Pre), during (Mid), and after (Post) the energy deficit were determined using heavy water (days 1-42) and muscle biopsies. Muscle mass was determined using the D3-creatine dilution method. RESULTS: Mixed-MPS was lower than Pre at Mid and Post (P < 0.0005), with no difference between TEST and PLA. The proportion of individual proteins with numerically higher FSR in TEST than PLA was significant by 2-tailed binomial test at Post (52/67; P < 0.05), but not Mid (32/67; P > 0.05). Muscle mass was unchanged during energy deficit but was greater in TEST than PLA during recovery (P < 0.05). CONCLUSIONS: The high proportion of individual proteins with greater FSR in TEST than PLA at Post suggests exogenous testosterone exerted a delayed but broad stimulatory effect on synthesis rates across the muscle proteome during energy deficit, resulting in muscle mass accretion during subsequent recovery.

Sca-1 influences the innate immune response during skeletal muscle regeneration.

Efficient muscle regeneration requires the clearance of dead and dying tissue via phagocytosis before remodeling. We have previously shown that mice lacking stem cell antigen-1 (Sca-1) display a defect in skeletal muscle regeneration characterized by increased fibrosis and decreased turnover of the extracellular matrix. In the present study we demonstrate that Sca-1(-/-) mice have a defect in their capacity to recruit soluble IgM, and subsequently C3 complement, to damaged muscle. We hypothesize that this defect in recruitment delays or decreases phagocytosis by macrophages, contributing to the previously observed fibrotic phenotype of these mice. As the primary source of soluble IgM is peritoneal B-1a cells, which are a subset of self-renewing B cells, we analyzed this cell population and observed a significant reduction in B-1a cells in Sca-1(-/-) animals. Interestingly, these mice are protected from ischemia-reperfusion injury, an acute inflammatory reaction also mediated by IgM and C3 complement that has been linked to a deficit in B-1a cells in previous studies. Collectively, these data reveal a novel role for Sca-1 in innate immunity during muscle regeneration and indicate that further elucidation of immuno-myogenic processes will help to better understand and promote muscle regeneration.

Identification of serum biomarkers for aging and anabolic response.

OBJECTIVE: With the progressive aging of the human population, there is an inexorable decline in muscle mass, strength and function. Anabolic supplementation with testosterone has been shown to effectively restore muscle mass in both young and elderly men. In this study, we were interested in identifying serum factors that change with age in two distinct age groups of healthy men, and whether these factors were affected by testosterone supplementation. METHODS: We measured the protein levels of a number of serum biomarkers using a combination of banked serum samples from older men (60 to 75 years) and younger men (ages 18 to 35), as well as new serum specimens obtained through collaboration. We compared baseline levels of all biomarkers between young and older men. In addition, we evaluated potential changes in these biomarker levels in association with testosterone dose (low dose defined as 125 mg per week or below compared to high dose defined as 300 mg per week or above) in our banked specimens. RESULTS: We identified nine serum biomarkers that differed between the young and older subjects. These age-associated biomarkers included: insulin-like growth factor (IGF1), N-terminal propeptide of type III collagen (PIIINP), monokine induced by gamma interferon (MIG), epithelial-derived neutrophil-activating peptide 78 (ENA78), interleukin 7 (IL-7), p40 subunit of interleukin 12 (IL-12p40), macrophage inflammatory protein 1ß (MIP-1ß), platelet derived growth factor ß (PDGFß) and interferon-inducible protein 10 (IP-10). We further observed testosterone dose-associated changes in some but not all age related markers: IGF1, PIIINP, leptin, MIG and ENA78. Gains in lean mass were confirmed by dual energy X-ray absorptiometry (DEXA). CONCLUSIONS: Results from this study suggest that there are potential phenotypic biomarkers in serum that can be associated with healthy aging and that some but not all of these biomarkers reflect gains in muscle mass upon testosterone administration.

Pressing Questions and Challenges in the HIV-1 and SARS-CoV-2 Syndemic.

Since emerging into the human population in late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has reached across the globe to infect >80 million people. The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 can range in severity from mild and asymptomatic to severe and fatal. Identifying risk factors for adverse outcomes in COVID-19 is a major challenge. In the context of the existing HIV-1 pandemic, whether COVID-19 disproportionately burdens people living with HIV-1 infection (PLWH) is unclear. The following discussion highlights pressing questions and challenges in the HIV-1 and SARS-CoV-2 syndemic, including (i) age, sex, and race as drivers of COVID-19 severity; (ii) whether chronic inflammation common in PLWH influences immune response; (iii) whether disease severity and trajectory models for COVID-19 ought to be calibrated for PLWH; (iv) vaccine considerations, and finally, (v) long-term health outcomes in PLWH that are further burdened by coinfection with SARS-CoV-2.