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Rationale and Objective: Glomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFRcr-cys) is more accurate than estimated GFR (eGFR) based on creatinine or cystatin C alone (eGFRcr or eGFRcys, respectively), but the inclusion of creatinine in eGFRcr-cys requires specification of a person's race. beta 2-Microglobulin (B2M) and beta-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine is.Study Design: Study of diagnostic test accuracy.Setting and Participants: Development in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants. Tests Compared: Panel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race. Outcomes: GFRmeasured as the urinary clearance of iothalamate, plasmaclearanceof iohexol, orplasma clearance of [Cr-51]EDTA.Results: Mean measured GFRs were 58.1 and 83.2 mL/min/1.73 m(2), and the proportions of Black participants were 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared with equations without age and sex, but addition of race did not further improve the performance. In validation, the 4-marker panels were more accurate than the 3-marker panels (P < 0.001). The 3-marker panel without race was more accurate than eGFRcys (percentage of estimates greater than 30% different from measured GFR [1-P30] of 15.6% vs 17.4%; P = 0.01), and the 4-marker panel without race was as accurate as eGFRcr-cys (1-P-30 of 8.6% vs 9.4%; P = 0.2). Results were generally consistent across subgroups.Limitations: No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe.Conclusions: The 4-marker panel eGFR is as accurate as eGFRcr-cys without requiring specification of race. A more accurate race-free eGFR could be an important advance.

Background C-reactive protein (CRP) is an inflammatory biomarker associated with all-cause mortality and morbidities such as cardiovascular disease. CRP is increased with HIV infection and thought to increase with age, though trajectories of CRP with aging have not been well characterized. We investigated trajectories of CRP in men from the Multicenter AIDS Cohort Study, according to HIV infection and HIV viral load status. Methods CRP measurements from 12 250 serum samples, provided by 2132 men over a span of 30 years, were categorized by HIV status at sample collection: HIV uninfected (HIV−, n = 1717), HIV infected with undetectable RNA (HIV+ suppressed, n = 4075), and detectable HIV RNA (HIV+ detectable, n = 6458). Age-related trajectories of CRP were fit to multivariable linear mixed models; we tested for differences in trajectories by HIV status. Results CRP increased with age in all sample groups. HIV+ detectable and HIV+ suppressed samples had higher CRP than HIV− samples throughout the observed age range of 20–70 years (p < .05). CRP concentrations at age 45 years were 38% (95% CI: 26%–50%) and 26% (15%–38%) higher in HIV+ detectable and HIV+ suppressed samples, respectively, relative to HIV− samples. HIV+ detectable samples showed more rapid linear increases with age (8% higher/decade, 0.3%–16%) than HIV− samples. Conclusions We observed higher concentrations of CRP across 5 decades of age in men living with HIV, and steeper increases with age in men with detectable HIV RNA, relative to HIV− men. These results are consistent with a contribution of inflammation to the higher risk of age-related comorbidities with HIV infection.

With increasing effectiveness of antiretroviral therapy, people with HIV (PWH) are living longer and the prevalence of older PWH continues to increase. Accordingly, PWH are experiencing an increased burden of age-related comorbidities. With this shifting demographics, clinicians and researchers face additional challenges in how to identify, address, and manage the complex intersections of HIV- and aging-related conditions. Established in 2009, the International Workshop on HIV and Aging brings together clinicians and researchers in cross-disciplinary fields along with community advocates and PWH to address the multidisciplinary nature of HIV and aging. This article summarizes plenary talks from the 10th Annual International Workshop on HIV and Aging, which took place in New York City on October 10 and 11, 2019. Presentation topics included the following: the burdens of HIV-associated comorbidities, aging phenotypes, community engagement, and loneliness; these issues are especially important for older PWH, considering the current COVID-19 pandemic. We also discuss broad questions and potential directions for future research necessary to better understand the interaction between HIV and aging.

The Martin-Hopkins equation used to calculate low-density lipoprotein cholesterol (LDL-C) is more accurate than the traditional Friedewald equation, especially at higher triglyceride levels, which are more common in people with HIV (PWH). Thus, using LDL-C values calculated by the Martin-Hopkins equation may improve clinical care of PWH.

Background People living with human immunodeficiency virus (HIV; PLWH) have a markedly elevated anal cancer risk, largely due to loss of immunoregulatory control of oncogenic human papillomavirus infection. To better understand anal cancer development and prevention, we determined whether recent, past, cumulative, or nadir/peak CD4+ T-cell count (CD4) and/or HIV-1 RNA level (HIV RNA) best predict anal cancer risk. Methods We studied 102 777 PLWH during 1996–2014 from 21 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. Using demographics-adjusted, cohort-stratified Cox models, we assessed associations between anal cancer risk and various time-updated CD4 and HIV RNA measures, including cumulative and nadir/peak measures during prespecified moving time windows. We compared models using the Akaike information criterion. Results Cumulative and nadir/peak CD4 or HIV RNA measures from approximately 8.5 to 4.5 years in the past were generally better predictors for anal cancer risk than their corresponding more recent measures. However, the best model included CD4 nadir (ie, the lowest CD4) from approximately 8.5 years to 6 months in the past (hazard ratio [HR] for Conclusions Our results are consistent with anal cancer promotion by severe, prolonged HIV-induced immunosuppression. Nadir and cumulative CD4 may represent useful markers for identifying PLWH at higher anal cancer risk.

Semen exosomes (SE) from HIV-uninfected (HIV&minus, ) individuals potently inhibit HIV infection in vitro. However, morphological changes in target cells in response to SE have not been characterized or have the effect of HIV infection or the use of illicit substances, specifically psychostimulants, on the function of SE been elucidated. The objective of this study was to evaluate the effect of HIV infection, psychostimulant use, and both together on SE-mediated regulation of monocyte function. SE were isolated from semen of HIV&minus, and HIV-infected (HIV+) antiretroviral therapy (ART)-naive participants who reported either using or not using psychostimulants. The SE samples were thus designated as HIV&minus, Drug&minus, HIV&minus, Drug+, HIV+Drug&minus, and HIV+Drug+. U937 monocytes were treated with different SEs and analyzed for changes in transcriptome, morphometrics, actin reorganization, adhesion, and chemotaxis. HIV infection and/or use of psychostimulants had minimal effects on the physical characteristics of SE. However, different SEs had diverse effects on the messenger RNA signature of monocytes and rapidly induced monocyte adhesion and spreading. SE from HIV infected or psychostimulants users but not HIV&minus, SE, stimulated actin reorganization, leading to the formation of filopodia-like structures and membrane ruffles containing F-actin and vinculin that in some cases were colocalized. All SE stimulated monocyte chemotaxis to HIV secretome and activated the secretion of matrix metalloproteinases, a phenotype exacerbated by HIV infection and psychostimulant use. SE-directed regulation of cellular morphometrics and chemotaxis depended on the donor clinical status because HIV infection and psychostimulant use altered SE function. Although our inclusion criteria specified the use of cocaine, humans are poly-drug and alcohol users and our study participants used psychostimulants, marijuana, opiates, and alcohol. Thus, it is possible that the effects observed in this study may be due to one of these other substances or due to an interaction between different substances.

BackgroundFactors affecting kidney function and proteinuria among HIV-positive (HIV+) and HIV-negative (HIV-) persons need better characterization.MethodsWe evaluated estimated glomerular filtration rate (eGFR, ml/min per 1.73 m) changes, proteinuria prevalence (a urine protein-to-creatinine ratio of ≥0.2 at two consecutive visits) and associated factors among HIV+ and HIV- men.ResultsThere were 917 HIV+ men receiving HAART, 159 HIV+ men not receiving HAART, and 1305 HIV- men seen from October 2003 to September 2014. Median annual eGFR change was -0.5, -0.8% for HIV+ and -0.3% for HIV- men (P

BACKGROUND: Age-related gait speed decline is accelerated in men with human immunodeficiency virus (HIV). Mitochondrial genetic variation is associated with frailty and mortality in the general population and may provide insight into mechanisms of functional decline in people aging with HIV. METHODS: Gait speed was assessed semiannually in the Multicenter AIDS Cohort Study. Mitochondrial DNA (mtDNA) haplogroups were extracted from genome-wide genotyping data, classifying men aged ≥50 years into 5 groups: mtDNA haplogroup H, J, T, Uk, and other. Differences in gait speed by haplogroups were assessed as rate of gait speed decline per year, probability of slow gait speed (

As individuals with human immunodeficiency virus (HIV) infection live longer, aging and age-related chronic conditions have become major health concerns for this vulnerable population. Substantial evidence suggests that chronic inflammation and immune activation contribute significantly to chronic conditions in people aging with or without HIV infection. As a result, increasing numbers of inflammation and immune activation biomediators have been measured. While very few studies describe their in vivo relationships, such studies can serve as an important and necessary initial step toward delineating the complex network of chronic inflammation and immune activation. In this study, we evaluated in vivo relationships between serum levels of neopterin, a biomediator of immune activation, and four commonly described inflammatory biomediators: soluble tumor necrosis factor (TNF)-α receptor (sTNFR)-1, sTNFR-2, interleukin (IL)-6, and C-reactive protein (CRP), as well as the impact of HIV infection and aging in the AIDS Linked to the Intravenous Experience (ALIVE) study, a community-recruited observational study of former and current injection drug users (IDUs) with or at high risk for HIV infection in Baltimore, MD, USA. The study included 1,178 participants in total with 316 HIV-infected (HV+) and 862 HIV-uninfected (HIV−) IDUs. Multivariate regression analyses were employed, adjusting for age, sex, body mass index, smoking, hepatitis C virus co-infection, injection drug use, comorbidities, and HIV status (for all participants), and HIV viral load, CD4+ T-cell counts, and antiretroviral therapy (for HIV+ participants). The results showed significant impact of aging on all five biomediators and that of HIV infection on all but sTNFR-1. In the adjusted model, neopterin had positive associations with sTNFR-1 and sTNFR-2 (partial correlation coefficients: 0.269 and 0.422, respectively, for all participants; 0.292 and 0.354 for HIV+; and 0.262 and 0.435 for HIV−, all p

Background and aimsFrailty and cardiovascular disease share many risk factors. We evaluated whether frailty is independently associated with subclinical coronary atherosclerosis and whether any relationships differ by HIV-serostatus.MethodsWe studied 976 [62% HIV-infected] male participants of the Multicenter AIDS Cohort Study who underwent assessment of frailty and non-contrast cardiac CT scanning; of these, 747 men also underwent coronary CT angiography (CCTA). Frailty was defined as having ≥3 of 5 of the following: weakness, slowness, weight loss, exhaustion, and low physical activity. Coronary artery calcium (CAC) was assessed by non-contrast CT, and total plaque score (TPS), mixed plaque score (MPS), and non-calcified plaque score (NCPS) by CCTA. Multivariable-adjusted regression was used to assess the cross-sectional associations between frailty and subclinical coronary atherosclerosis.ResultsMean (SD) age of participants was 54 (7) years; 31% were black. Frailty existed in 7.5% and 14.3% of HIV-uninfected and HIV-infected men, respectively. After adjustment for demographics, frailty was significantly associated with prevalence of any CAC (CAC>0), any plaque (TPS>0), and mixed plaque (MPS>0) in HIV-uninfected but not in HIV-infected men (p-interactionHIV0 [Prevalence Ratio 1.27 (95%CI 1.02, 1.59)] and TPS>0 [1.19 (1.06, 1.35)]. No association was found for NCPS.ConclusionsFrailty was independently associated with subclinical coronary atherosclerosis among HIV-uninfected men, but not among HIV-infected men. Further work is needed to ascertain mechanisms underlying these differences and whether interventions that improve frailty (i.e. strength training) can improve cardiovascular outcomes.

BACKGROUND Frailty is associated with immune activation and inflammation in the elderly general population, but whether this is true in the younger HIV-infected (HIV+) population is not known. METHODS We analyzed 24 serologic biomarkers of monocyte, T-cell, or B-cell activation in HIV- (n = 207) and HIV+ (n = 714; 75% virologically suppressed) men who have sex with men in the Multicenter AIDS Cohort Study (MACS) and were classified as frail or nonfrail according to expression or nonexpression of the frailty phenotype at 2 consecutive study visits. RESULTS After correction for multiple comparisons and adjustment for age, race, study site, and education, frailty in HIV+ men was significantly (P < 0.002) associated with higher levels of sCD14, sIL2Rα, sTNF-R2, IL-6, and TNF-α; the association with higher levels of C-reactive protein (CRP) approached significance (P = 0.003). After further adjustment for body mass index (BMI), smoking, and comorbidities, only the association with C-reactive protein was significant at P < 0.002, with levels approximately 50% higher in frail compared with nonfrail men. These conclusions were not altered by restricting the analysis to HIV+ men who were virologically suppressed. Among HIV- men, none of these markers differed significantly by frailty. CONCLUSIONS These data suggest that frailty in virologically suppressed HIV+ men was associated with immune activation beyond that due to treated HIV infection. The inflammatory markers associated with frailty were primarily products of activated monocytes/macrophages. Much, but not all, activation was accounted for by harmful behaviors and comorbidities. However, C-reactive protein, which is regulated by IL-6, was elevated in HIV+ frail men independent of these factors.

Energy utilization becomes more inefficient with age and is linked to low physical activity and functional decline. Persons aging with HIV exhibit accelerated functional decline, but the effect of chronic HIV infection on energy utilization and free-living physical activity remains unclear. We investigated cross-sectional associations between age and: resting metabolic rate, peak walking energy (VO2), and 7-day physical activity by accelerometry in 100 men in the MACS (age: 60.8+/-6.8 years, 35% black, 46.1% HIV+, 94% virally suppressed). In multivariable regression models adjusted for age, BMI, race, chronic conditions, and HIV viral load, HIV+ men had a higher resting metabolic rate (β=103.2 kcals/day, p=0.03) and lower peak walking VO2 (β=-1.8 ml/kg/min, p

Exosomes are important vehicles of intercellular communication that shape host responses to physiologic, tumorigenic, and pathogenic conditions. The composition and function of exosomes are dynamic and depends on the state and condition of the cellular source. In prior work, we found that semen exosomes (SE) from healthy donors who do not use illicit drugs potently inhibit HIV-1. Following semen donation, specimens are either used immediately or frozen for use at a later time. It has been shown that short-term freezing of semen has no effect on SE-mediated HIV-1 inhibition. However, the effect of illicit drugs and prolonged freezing on SE bioactivity is unknown. Here, we show preservation of SE physical properties, (morphology, concentration, intensity/size) irrespective of illicit drug use or duration of semen freezing. Interestingly, illicit drugs and prolonged freezing decreased the levels of SE-bound CD63/CD9 and acetylcholinesterase activity respectively. Furthermore, we show differential effects of illicit drug use and prolonged freezing on SE-mediated HIV-1 inhibition. Our results highlight the importance of the source of SE and condition of semen storage on SE content and function. In-depth evaluation of donor drug-use and duration of semen storage on SE cargo and bioactivity will advance our understanding of SE composition and function.

We evaluated associations of serum 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]2D) levels in a cohort of HIV-infected and HIV-uninfected men at risk for infection in the United States. Stored samples collected between 1999 and 2008 were tested for vitamin D metabolites between 2014 and 2015. Vitamin D deficiency was defined as a serum concentration of 25[OH]D

BACKGROUND Lower muscle density on computed tomography (CT) provides a measure of fatty infiltration of muscle, an aspect of muscle quality that has been associated with metabolic abnormalities, weakness, decreased mobility, and increased fracture risk in older adults. We assessed the cross-sectional relationship between HIV serostatus, age, thigh muscle attenuation, and thigh muscle cross-sectional area (CSA). METHODS Mean CT-quantified Hounsfield units (HU) of the thigh muscle bundle and CSA were evaluated in 368 HIV-infected and 145 HIV-uninfected men enrolled in the Multicenter AIDS Cohort Study (MACS) Cardiovascular Substudy using multivariable linear regression. Models all were adjusted for HIV serostatus, age, race, and body mass index (BMI); each model was further adjusted for covariates that differed by HIV serostatus, including insulin resistance, hepatitis C, malignancy, smoking, alcohol use, and self-reported limitation in physical activity. RESULTS HIV-infected men had greater thigh muscle CSA (p

PurposePersistent oral human papillomavirus (HPV) infection increases risk for oropharyngeal carcinoma, and people living with HIV have higher rates of oral HPV infection and related cancers. Some prescription medications have immunomodulatory effects, but the impact of medication use on oral HPV natural history is unknown.MethodsScope® oral rinse-and-gargle samples were collected semi-annually from 1,666 participants and tested for 37 types of oral HPV DNA using PCR; 594 HPV-infected participants with 1,358 type-specific oral HPV infections were identified. Data were collected on recent (past 6months) use of medications. The relationship between medication use and oral HPV clearance was evaluated using Wei-Lin-Weissfeld regression, adjusting for biologic sex, prevalent versus incident infection, age, HIV status and CD4+T cell count.ResultsOut of 11 medications examined, oral HPV clearance was significantly reduced in participants reporting recent use of antipsychotics (HR 0.75, 95% CI 0.57-0.99), anxiolytics/sedatives (HR 0.78, 95% CI 0.63-0.96) and antidepressants (HR 0.82, 95% CI 0.67-0.999). Among antipsychotics users, effect modification by HIV status was observed, with reduced clearance in HIV-infected (HR 0.67, 95% CI 0.49-0.91), but not HIV-uninfected participants (p-interaction=0.009). After adjusted analysis, antipsychotic use remained significantly associated with reduced oral HPV clearance overall (aHR 0.75, 95% CI 0.57-0.99), and when restricted to only HIV-infected participants (aHR 0.66, 95% CI 0.48-0.90). After adjustment, anxiolytic/sedative use and antidepressant use were no longer significantly associated with reduced oral HPV clearance.ConclusionsSome medications were associated with decreased oral HPV clearance, most notably antipsychotic medications. These medications are prescribed for conditions that may have immunomodulating effects, so characteristics of underlying illness may have partially contributed to reduced oral HPV clearance.

OBJECTIVE Grip strength predicts functional decline and death, and is regarded as a biomarker of biological aging. The primary objective of this manuscript was to assess differences in the rate of decline in grip strength in persons aging with and without HIV. DESIGN Grip strength was assessed in 1552 (716 HIV+ and 836 HIV-) men aged at least 50 years participating in the Multicenter AIDS Cohort Study between 2007 and 2014. METHODS Grip strength decline was modeled longitudinally, adjusting for serostatus, demographics, comorbidities, and conditions. In HIV-specific models, coefficients were included for cumulative viral load and history of AIDS. RESULTS Grip strength at the age of 50 years averaged 37.9 and 38.2 kg for HIV+ and HIV- men, respectively (P = 0.70). In fully adjusted models, grip strength declined 0.33 kg/year in HIV- men (P

Background Human immunodeficiency virus (HIV)-induced inflammation and immune activation persist after initiation of combination antiretroviral therapy (cART) and HIV suppression and may contribute to mortality risks that exceed those in HIV-uninfected populations, though associations are unclear. Methods In the prospective Multicenter AIDS Cohort Study, comprising men who have sex with men from Baltimore, Chicago, Los Angeles, and Pittsburgh, concentrations of 24 biomarkers of inflammation and immune activation were measured in stored serum from HIV-positive men obtained after cART-induced HIV suppression between 1996 and 2009. The outcome was nonaccidental death, with follow-up until 2014. We used Cox proportional hazards models to test whether biomarker concentrations predict time from HIV suppression to death and adjusted for multiple tests. Exploratory factor analysis (EFA) was employed to identify groupings of biomarkers that predict mortality risk. Results Of 670 men followed up from HIV suppression, 54 died by the end of 2013. After adjustment for age, CD4(+) cell count, hepatitis B or C virus infection, and smoking, concentrations in the highest quartile of 4 biomarkers were significantly associated with mortality risk after controlling the false discovery rate at 5%: interleukin (IL) 6 (hazard ratio, 3.54; 95% confidence interval, 2.06-6.10), soluble IL 2Rα (3.29, 1.85-5.85), soluble CD14 (2.67, 1.55-4.61), and chemokine (CXC motif) ligand 13 (CXCL13; 2.26; 1.29-3.95). EFA yielded 2 biomarker groupings that were independent predictors of mortality risk. Conclusions Despite having undetectable HIV RNA levels during cART, men with higher concentrations of several biomarkers (particularly IL 6, soluble IL 2Rα, soluble CD14, and CXCL13) had higher hazards of long-term mortality. Correlations observed among biomarker concentrations may represent underlying inflammatory processes that contribute to mortality risk.

In the United States, approximately 5% of the population is malnourished or has low body weight, which can adversely affect immune function. Malnutrition is more prevalent in older adults and is often a result of energy imbalance from various causes. Dietary supplementation to promote positive energy balance can reverse malnutrition, but has not been assessed for its effect on immune parameters. This 8-week clinical feeding trial evaluated the effect of a commercially available, high-protein, high-energy formula on body weight and immune parameters in 30 adult volunteers with body-mass indices (BMI) 2. After the intervention, participants gained a mean of 3.74 lbs and increased BMI by 0.58 kg/m2. The intervention improved lean body mass and limited body fat accumulation. However, no clinically significant improvements in immune measures were observed. These results support the use of high-protein, high-energy supplements in the treatment of underweight/malnutrition. Further investigation utilizing feeding studies of longer duration, and/or studying severely malnourished individuals may be needed to detect an effect on immune parameters of weight gain promoted by nutritional supplements.

Understanding the characteristics of human immunodeficiency virus (HIV) necessary for infection in a new host is a critical goal for acquired immunodeficiency syndrome (AIDS) research. We studied the characteristics of HIV-1 envelope genes in 38 men in the Multicenter AIDS Cohort Study cohort before seroconversion. We found a range of diversity (0.2%-5.6% [median, 0.86%]), V1-V2 loop length (58-93 aa), and potential N-linked glycosylation sites (n = 2-9). However, at least 46% of the men had replicating virus that appeared to have been derived from a single viral variant. Nearly all variants were predicted to be CCR5 tropic. We found no correlation between these viral characteristics and the HIV outcomes of time to clinical AIDS or death and/or a CD4 cell count

Aging in males is associated with lower testosterone levels and a decrease in diurnal variation of testosterone secretion. Cross-sectional studies have shown lower than expected testosterone levels among HIV-infected men, but whether age-related changes in serum testosterone differ by HIV serostatus are not known.HIV-infected men from the Multicenter AIDS Cohort Study (MACS), age ≥ 45 years at highly active antiretroviral therapy initiation, who had ≥ 2 samples from the subsequent 10 years, were matched to HIV-uninfected men by age, race, MACS site, and calendar time of samples. Linear mixed-effects regression models were used to determine whether free testosterone (FT) and its rate of change differed by HIV serostatus.One hundred eighty-two HIV-infected and 267 HIV-uninfected men were included, median age: 48.8 years (interquartile range: 45.8-53.4), median numbers of FT measurements per participant 4 (interquartile range: 3-5), 65% were drawn in the adjusted morning (AM). Mean-adjusted FT levels were lower among HIV-infected than HIV-uninfected men in AM samples {-6.1 ng/dL [95% confidence interval (CI): -9.8 to -2.4], P = 0.001}, but not in afternoon samples [-1.7 ng/dL (-6.0 to 2.6), P = 0.441]. The rate of FT decline with age did not differ by HIV serostatus: 9.2 ng/dL (95% CI: -13.4 to -5.0) per 10 years for HIV-infected vs. 7.9 ng/dL (95% CI: -10.2 to -5.5) for HIV-uninfected men, P = 0.578.FT decreased similarly with increasing age regardless of HIV serostatus. The lower AM, but not adjusted afternoon, FT levels among HIV-infected men compared with HIV-uninfected men suggest a loss of diurnal variation in FT levels among HIV-infected men.

Background Both HIV infection and frailty have been associated with chronic immune activation. One possible explanation for this chronic immune activation could be low levels of CD4(+) T regulatory cells (Tregs), which suppress immune responses. Methods HIV-uninfected (HIV-) and HIV-infected (HIV+) men in the Multicenter AIDS Cohort Study (MACS) were classified as frail (or nonfrail) if they expressed (or did not express) the Fried frailty phenotype at two consecutive study visits. Percentages and absolute numbers of total Tregs, and percentages of different subsets of Tregs and of activated T cells were measured by flow cytometry. The function of Tregs was measured by suppression of T-cell proliferation. Results Percentages of Tregs were higher, rather than lower, in frail men than in nonfrail men, and this difference was significant for HIV- men. Percentages of subsets of Tregs did not differ significantly by frailty status. Among HIV+ men, the suppressive function of Tregs was similar between frail and nonfrail men. Percentages of Tregs and activated T cells were negatively correlated in nonfrail men (HIV- and HIV+) and in frail HIV- men, but this correlation was strongly positive in frail HIV+ men. Conclusion These data suggest that: (a) Tregs were not deficient in frail men; and (b) the immunological pathophysiology of frailty may differ by HIV status.

BackgroundHuman papillomavirus (HPV) types 16 and 18 cause invasive cervical cancer and most invasive anal cancers (IACs). Overall, IAC rates are highest among men who have sex with men (MSM), especially MSM with HIV infection. Testosterone is prescribed for men showing hypogonadism and HIV-related wasting. While there are direct and indirect physiological effects of testosterone in males, its role in anal HPV16/18 infections in men is unknown.MethodsFree testosterone (FT) was measured in serum from 340 Multicenter AIDS Cohort Study (MACS) participants who were tested for anal HPV16/18-DNA approximately 36 months later. The effect of log10-transformed current FT level on anal HPV16/18 prevalence was modeled using Poisson regression with robust error variance. Multivariate models controlled for other HPV types, cumulative years of exogenous testosterone use, race, age, lifetime number of receptive anal intercourse partnerships, body mass index, tobacco smoking, HIV-infection and CD4+ T-cell counts among HIV-infected, and blood draw timing.ResultsParticipants were, on average, 60 (+5.4) years of age, White (86%), and HIV-uninfected (56%); Twenty-four percent tested positive for anal HPV16 and/or 18-DNA (HPV16 prevalence=17.1%, HPV18=9.1%). In adjusted analysis, each half-log10 increase of FT was associated with a 1.9-fold (95% Confidence Interval: 1.11, 3.24) higher HPV16/18 prevalence. Additionally, other Group 1 high-risk HPVs were associated with a 1.56-fold (1.03, 2.37) higher HPV16/18 prevalence. Traditional risk factors for HPV16/18 infection (age, tobacco smoking; lifetime number of sexual partners, including the number of receptive anal intercourse partnerships within 24 months preceding HPV testing) were poorly correlated with one another and not statistically significantly associated with higher prevalence of HPV16/18 infection in unadjusted and adjusted analyses.ConclusionsHigher free testosterone was associated with increased HPV16/18 prevalence measured approximately three years later, independent of sexual behavior and other potential confounders. The mechanisms underlying this association remain unclear and warrant further study.

Background It has been proposed that initiation of antiretroviral treatment (ART) very soon after establishment of HIV infection may be beneficial by improving host control of HIV replication and delaying disease progression. Methods People with documented HIV infection of less than 12 months’ duration in Baltimore MD and seven Canadian sites were randomized to either a) observation and deferred ART, or b) immediate treatment with ART for 12 months. All subjects not receiving ART were followed quarterly and permanent ART was initiated according to contemporaneous treatment guidelines. The endpoint of the trial was total ART-free time from study entry until initiation of permanent ART. Results One hundred thirteen people were randomized, 56 to the observation arm and 57 to the immediate treatment arm. Twenty-three had acute (

Background: Multi-assay algorithms (MAAs) can be used to estimate HIV incidence in cross-sectional surveys. We compared the performance of two MAAs that use HIV diversity as one of four biomarkers for analysis of HIV incidence. Methods: Both MAAs included two serologic assays (LAg-Avidity assay and BioRad-Avidity assay), HIV viral load, and an HIV diversity assay. HIV diversity was quantified using either a high resolution melting (HRM) diversity assay that does not require HIV sequencing (HRM score for a 239 base pair env region) or sequence ambiguity (the percentage of ambiguous bases in a 1,302 base pair pol region). Samples were classified as MAA positive (likely from individuals with recent HIV infection) if they met the criteria for all of the assays in the MAA. The following performance characteristics were assessed: (1) the proportion of samples classified as MAA positive as a function of duration of infection, (2) the mean window period, (3) the shadow (the time period before sample collection that is being assessed by the MAA), and (4) the accuracy of crosssectional incidence estimates for three cohort studies. Results: The proportion of samples classified as MAA positive as a function of duration of infection was nearly identical for the two MAAs. The mean window period was 141 days for the HRM-based MAA and 131 days for the sequence ambiguitybased MAA. The shadows for both MAAs were ,1 year. Both MAAs provided cross-sectional HIV incidence estimates that were very similar to longitudinal incidence estimates based on HIV seroconversion. Conclusions: MAAs that include the LAg-Avidity assay, the BioRad-Avidity assay, HIV viral load, and HIV diversity can provide accurate HIV incidence estimates. Sequence ambiguity measures obtained using a commercially-available HIV genotyping system can be used as an alternative to HRM scores in MAAs for cross-sectional HIV incidence estimation.

The mechanisms involved in the decline of CD4 and CD8 T-cells that lead to HIV-induced immune dysregulation are not clearly understood. We hypothesize that late-emerging strains of HIV, such as CXCR4-tropic (X4) virions, induce T-cell homeostasis failure by promoting significantly more bystander cell death, and immune exhaustion in naive CD4 and all CD8 T-cells, when compared to strain of HIV, such as CCR5-tropic (R5) virions, found early during the course of infection. In the reported study, inactivated X4 virions induced greater bystander cell death in sort-purified naive CD4 T-cells compared to R5 virions, which was significant ( p =0.013), and in memory CD8 T-cells, though the latter was not significant. A clearer understanding of the mechanisms involved in HIV-induced depletion of T-cell numbers and function could lead to therapies that prevent T-cell death and restore immune function. These therapies could improve current anti-retroviral and cure-related treatments by boosting the immune system's own ability to combat the virus.

OBJECTIVE To examine whether altered levels of adipokines, adipose-derived peptides associated with myocardial infarction in the general population, may contribute to subclinical coronary atherosclerosis in HIV-infected persons. DESIGN Nested cohort study. METHODS We studied HIV-infected (HIV+) and HIV-uninfected (HIV-) men in the Multicenter AIDS Cohort Study with noncontrast computed tomography (CT) to measure coronary artery calcium and regional adiposity; 75% additionally underwent coronary CT angiography to measure plaque composition and stenosis. Adiponectin and leptin levels were assessed. Multiple regression models were used to assess associations between adipokine levels and HIV disease parameters, regional adiposity, and plaque adjusted for age, race, HIV serostatus, and cardiovascular disease (CVD) risk factors. RESULTS Significant findings were limited to adiponectin. HIV-positive men (n=493) had lower adiponectin levels than HIV-negative men (n=250) after adjusting for CVD risk factors (P

ObjectiveFormulae used to estimate glomerular filtration rate (GFR) underestimate higher GFRs and have not been well-studied in HIV-infected (HIV(+)) people; we evaluated the relationships of HIV infection and known or potential risk factors for kidney disease with directly measured GFR and the presence of chronic kidney disease (CKD).DesignCross-sectional measurement of iohexol-based GFR (iGFR) in HIV(+) men (n = 455) receiving antiretroviral therapy, and HIV-uninfected (HIV(-)) men (n = 258) in the Multicenter AIDS Cohort Study.MethodsiGFR was calculated from disappearance of infused iohexol from plasma. Determinants of GFR and the presence of CKD were compared using iGFR and GFR estimated by the CKD-Epi equation (eGFR).ResultsMedian iGFR was higher among HIV(+) than HIV(-) men (109 vs. 106 ml/min/1.73 m(2), respectively, p = .046), and was 7 ml/min higher than median eGFR. Mean iGFR was lower in men who were older, had chronic hepatitis C virus (HCV) infection, or had a history of AIDS. Low iGFR (≤90 ml/min/1.73 m(2)) was associated with these factors and with black race. Other than age, factors associated with low iGFR were not observed with low eGFR. CKD was more common in HIV(+) than HIV(-) men; predictors of CKD were similar using iGFR and eGFR.ConclusionsiGFR was higher than eGFR in this population of HIV-infected and -uninfected men who have sex with men. Presence of CKD was predicted equally well by iGFR and eGFR, but associations of chronic HCV infection and history of clinically-defined AIDS with mildly decreased GFR were seen only with iGFR.

Background We sought to determine whether markers of systemic inflammation are associated with the presence of moderate/severe obstructive sleep apnea (OSA) and whether this association differs based on HIV and HIV treatment status. Methods HIV-uninfected men (HIV-; n=60), HIV-infected men receiving HAART (HIV+/HAART; n=58) and HIV-infected men not receiving HAART (HIV+/no HAART; n=41) underwent polysomnograpy and measurement of plasma levels of tumour necrosis factor (TNF)-α, soluble TNF-α receptors I and II (sTNFRI and sTNFRII) and interleukin (IL)-6. The relationship between moderate/severe OSA (respiratory disturbance index ≥15 apnea/hypopnea events/h) and inflammatory markers was assessed with multivariable regression models. Results Compared with the HIV- men, HIV+/HAART men and HIV+/no HAART men had higher levels of TNF-α>, sTNFRI and sTNFRII, independent of age, race, smoking status, obstructive lung disease (OLD) and body mass index (BMI). Moderate/severe OSA was present in 48% of the sample (HIV- 57%; HIV+/HAART 41%; HIV+/no HAART 44%). Among the HIV+/no HAART men, but not in the other groups, TNF-α, sTNFRII and IL-6 levels were higher in those with moderate/severe OSA compared to men with no/mild OSA after adjustment for age, race, smoking status, OLD and BMI. Within this group, the association of high TNF-α concentrations with moderate/ severe OSA was also independent of CD4+ T-cell count and plasma HIV RNA concentration. Conclusions Compared with HIV+/HAART men and HIV-men, markers of systemic inflammation were higher in HIV+/no HAART men. In these men, TNF-α was significantly related to OSA, independent of HIV-related covariates.

Increased expression of the voltage-gated potassium channel Kν1.3 on activated effector memory T cells (T(EM)) is associated with pathology in multiple sclerosis (MS). To date, most studies of Kν1.3 channels in MS have focused on CD4+ T(EM) cells. Much less is known about the functional relevance of Kv1.3 on CD8+ T(EM) cells. Herein, we examined the effects of Kν1.3 blockade on CD8+ T cell proliferation, differentiation into cytotoxic effector cells, and release of granzyme B (GrB), a key effector of CD8+ T cell-mediated cytotoxicity. We confirmed the expression of Kv1.3 channels on activated human CD8+ T lymphocytes by immunofluorescent staining. To test the functional relevance of the Kv1.3 channel in CD8+ T cells, we inhibited this channel via pharmacological blockers or a lentiviral-dominant negative (Kv1.xDN) approach and determined the effects of the blockade on critical pathogenic parameters of CD8+ T cells. We found that blockade of Kv1.3 with both lentivirus and pharmacologic agents effectively inhibited cytotoxic effector memory cells' proliferation, secretion of GrB, and their ability to kill neural progenitor cells. Intriguingly, the KvDN transduced T cells exhibited arrested differentiation from central memory (T(CM)) to effector memory (T(EM)) states. Transduction of cells that had already differentiated into T(EM) with KvDN led to their conversion into T(CM). CD8+ T(EM) have a critical role in MS and other autoimmune diseases. Our present results indicate a critical role for Kv1.3 in the conversion of CD8+ T cells into potential pathogenic effector cells with cytotoxic function.

Background: A limiting antigen avidity enzyme immunoassay (HIV-1 LAg-Avidity assay) was recently developed for crosssectional HIV incidence estimation. We evaluated the performance of the LAg-Avidity assay alone and in multi-assay algorithms (MAAs) that included other biomarkers. Methods and Findings: Performance of testing algorithms was evaluated using 2,282 samples from individuals in the United States collected 1 month to .8 years after HIV seroconversion. The capacity of selected testing algorithms to accurately estimate incidence was evaluated in three longitudinal cohorts. When used in a single-assay format, the LAgAvidity assay classified some individuals infected .5 years as assay positive and failed to provide reliable incidence estimates in cohorts that included individuals with long-term infections. We evaluated .500,000 testing algorithms, that included the LAg-Avidity assay alone and MAAs with other biomarkers (BED capture immunoassay [BED-CEIA], BioRadAvidity assay, HIV viral load, CD4 cell count), varying the assays and assay cutoffs. We identified an optimized 2-assay MAA that included the LAg-Avidity and BioRad-Avidity assays, and an optimized 4-assay MAA that included those assays, as well as HIV viral load and CD4 cell count. The two optimized MAAs classified all 845 samples from individuals infected .5 years as MAA negative and estimated incidence within a year of sample collection. These two MAAs produced incidence estimates that were consistent with those from longitudinal follow-up of cohorts. A comparison of the laboratory assay costs of the MAAs was also performed, and we found that the costs associated with the optimal two assay MAA were substantially less than with the four assay MAA. Conclusions: The LAg-Avidity assay did not perform well in a single-assay format, regardless of the assay cutoff. MAAs that include the LAg-Avidity and BioRad-Avidity assays, with or without viral load and CD4 cell count, provide accurate incidence estimates.

The BED capture enzyme immunoassay (BED-CEIA) was developed for estimating HIV incidence from cross-sectional data. This assay misclassifies some individuals with nonrecent HIV infection as recently infected, leading to overestimation of HIV incidence. We analyzed factors associated with misclassification by the BED-CEIA. We analyzed samples from 383 men who were diagnosed with HIV infection less than 1 year after a negative HIV test (Multicenter AIDS Cohort Study). Samples were collected 2–8 years after HIV seroconversion, which was defined as the midpoint between the last negative and first positive HIV test. Samples were analyzed using the BED-CEIA with a cutoff of OD-n ≤0.8 for recent infection. Logistic regression was used to identify factors associated with misclassification. Ninety-one (15.1%) of 603 samples were misclassified. In multivariate models, misclassification was independently associated with highly active antiretroviral treatment (HAART) for >2 years, HIV RNA 2 years of HAART were significantly associated with misclassification using the BED-CEIA. Some men were persistently misclassified as recently infected up to 8 years after HIV seroconversion.