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Data on the prevalence of sleep-disordered breathing (SDB) in people with HIV are limited. Moreover, whether the associations between SDB and age or BMI differ by HIV status is unknown.Is SDB more prevalent in men with HIV than those without HIV, and do the predictors of SDB differ between the two groups?Home polysomnography was used in the Multicenter AIDS Cohort Study to assess SDB prevalence in men with (n = 466; 92% virologically suppressed) and without (n = 370) HIV. SDB was defined using the oxygen desaturation index (ODI) and the apnea-hypopnea index (AHI), using four definitions: ≥ 5 events/h based on an ODI with a 3% (ODISDB prevalence was similar in men with and without HIV using the ODISDB prevalence was high overall but greater in men with than without HIV using the ODI

OBJECTIVES: People with HIV (PWH) are at increased risk for premature cardiovascular disease (CVD). Clonal hematopoiesis is a common age-related condition that may be associated with increased CVD risk. The goal of this study was to determine the prevalence of clonal hematopoiesis and its association with chronic inflammation and CVD in PWH. DESIGN: Cross-sectional study utilizing archived specimens and data from 118 men (86 PWH and 32 HIV-uninfected) from the Baltimore-Washington DC center of the Multicenter AIDS Cohort Study (MACS) who had had coronary computed tomography angiography (CTA) and measurement of 34 serologic inflammatory biomarkers. METHODS: Clonal hematopoiesis was assessed on peripheral blood mononuclear cells utilizing targeted error-corrected next generation sequencing (NGS) focused on 92 genes frequently mutated in hematologic malignancies. Clinical and laboratory data were obtained from the MACS database. RESULTS: Clonal hematopoiesis with a variant allele frequency (VAF) greater than 1% was significantly more common in PWH [20/86 (23.3%)] than in HIV-uninfected men [2/32 (6.3%)] (P = 0.035). PWH with clonal hematopoiesis (VAF > 1%) were more likely to have coronary artery stenosis of at least 50% than those without clonal hematopoiesis [6/20 (30%) vs. 6/64 (9%); P = 0.021]. Presence of clonal hematopoiesis was not significantly associated with serological inflammatory markers, except for significantly lower serum leptin levels; this was not significant after adjustment for abdominal or thigh subcutaneous fat area. CONCLUSION: Clonal hematopoiesis was more common in PWH and among PWH was associated with the extent of coronary artery disease. Larger studies are needed to further examine the biological and clinical consequences of clonal hematopoiesis in PWH.

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Introduction: Human papillomavirus (HPV) is an important risk factor for oropharyngeal cancer. Individuals with human immunodeficiency virus (HIV) have higher oral HPV prevalence but the risk factors for oral HPV infection are not well understood for either HIV-positive or HIV-negative individuals.Methods: This study was nested within the Multicenter AIDS Cohort Study (MACS; men) and Women Interagency HIV Study (WIHS; women) cohorts. Exfoliated oral epithelial cells were collected from 379 HIV-positive and 266 at-risk HIV-negative individuals using a rinse and gargle with Scope mouthwash. Samples were tested for 36 types of HPV DNA using PGMY09/11 consensus primers and reverse line blot hybridization. Risk factors for oral HPV infection were explored using logistic regression with generalized estimating equations in this cross-sectional analysis.Results: Prevalent oral HPV infection was common (34%), including HPV16 infection in 5.7% of participants. HIV-positive individuals had increased odds of prevalent oral HPV infection compared with HIV-negative individuals [adjusted OR = 2.1; 95% confidence interval (CI), 1.6–2.8]. Risk factors for prevalent oral HPV differed in HIV-positive and HIV-negative participants. Among HIV-negative individuals, higher number of recent oral sex or rimming partners were strong risk factors for prevalent oral HPV infection (each Ptrend < 0.01). In contrast, among HIV-positive individuals, lower CD4 T-cell count (Ptrend < 0.001) and higher number of lifetime sexual partners (Ptrend = 0.03) were strong risk factors.Conclusions: Oral HPV prevalence was elevated in HIV-positive individuals after controlling for differences in cigarette smoking and sexual behavior, supporting the possibility that HIV may affect the natural history of oral HPV.Impact: Immunosuppression may contribute to increased persistence or progression of oral HPV infection. Cancer Epidemiol Biomarkers Prev; 21(1); 122–33. ©2011 AACR.

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BACKGROUND Sex hormone-binding globulin (SHBG) is a glycoprotein that regulates sex hormone bioavailability and increases with age in the general population. SHBG concentrations are higher in people with HIV, a population in whom accelerated aging has been hypothesized. It is unclear whether longitudinal changes in SHBG increase over time and differ by HIV serostatus. METHODS In a longitudinal study, SHBG was measured in 182 men with HIV (MWH) and 267 men without HIV (seronegative) from the Multicenter AIDS Cohort Study and matched for age, race, site, and time, with ≥2 SHBG serum samples over the 10 years after HAART initiation. Multivariable linear mixed-effects regression models were used to evaluate whether log-transformed SHBG [ln(SHBG)] and its rate of change differed by HIV serostatus. RESULTS At baseline, the mean age in MWH was similar to that in HIV-seronegative men (51 ± 5 vs 49 ± 6 years). However, SHBG mean values were higher in MWH compared with those in HIV-seronegative men (65.6 ± 48.8 vs. 45.4 ± 22 nmol/L, P < 0.001). In a fully adjusted model, SHBG increased over time and at a faster rate in MWH compared with that in HIV-seronegative men: [2.0%/year (95% CI: 1.4 to 2.7) vs 1.3%/year (95% CI: 0.8 to 1.8), respectively, P = 0.038]. Among MWH, higher SHBG concentrations were significantly associated with lower CD4+ T-cell count [β= -0.02 (95% CI: -0.03 to -0.0002), P < 0.05], fewer cumulative years on zidovudine [β = -0.027 (95% CI: -0.045 to -0.009), P < 0.001], and greater cumulative years on nonnucleoside reverse transcriptase inhibitors drugs [β = 0.022 (95% CI: 0.0006 to 0.04), P < 0.05]. CONCLUSIONS Aging-related increases in SHBG were faster in MWH compared with those in HIV-seronegative men and were related to poorer immunologic status and antiretroviral medication exposure. The mechanisms and consequences of these findings require further investigation.

Background Infection with human immunodeficiency virus (HIV) is associated with higher risk for myocardial disease despite modern combination antiretroviral therapy (cART). Factors contributing to this excess risk, however, remain poorly characterized. We aimed to assess cross-sectional relationships between elevations of left atrial volume index (LAVI) and myocardial extracellular volume (ECV) fraction that have been reported in persons living with HIV and levels of circulating biomarkers of inflammation, fibrosis, and myocyte stretch among persons living with and without HIV (PLWH, PLWOH). Methods Participants from three cohorts of PLWH and PLWOH underwent cardiovascular magnetic resonance imaging for measurement of LAVI and ECV. Levels of circulating proteins (IL-6, sCD14, galectin-3, NT-proBNP, GDF-15, TIMP-2, MMP-2, and hsTnI) were measured using immunoassays. Associations were assessed using logistic and linear regression, adjusting for demographics, substance use, and clinical characteristics. Results Among 381 participants with and without HIV, median age (IQR) was 55.1 (51.2, 58.4) years, 28% were female, 69% were Black, and 46% were current smokers. Sixty-two percent were PLWH (n = 235), of whom 88% were receiving cART and 72% were virally suppressed. PLWH had higher levels of sCD14 (p = p = p = 0.03) compared to PLWOH, while levels of other biomarkers did not differ by HIV serostatus, including IL-6 (p = 0.84). Among PLWH, higher sCD14, GDF-15, and NT-proBNP were also associated with lower CD4 + cell count, and higher NT-proBNP was associated with detectable HIV viral load. NT-proBNP was associated with elevated LAVI (OR: 1.79 [95% CI: 1.31, 2.44]; p Conclusions Our findings suggest that elevated levels of sCD14, GDF-15, and NT-proBNP among PLWH compared to PLWOH observed in the current cART era may only minimally reflect HIV-associated elevations in LAVI and ECV. Future studies of excess risk of myocardial disease among contemporary cohorts of PLWH should investigate mechanisms other than those connoted by the studied biomarkers.

Background and aimsPeople living with HIV (HIV+) are surviving longer due to effective antiretroviral therapy. Cardiovascular disease is a leading cause of non-AIDS related clinical events. We determined HIV-related factors associated with coronary artery stenosis progression.MethodsWe performed serial coronary CT angiography among HIV+ and HIV-uninfected (HIV-) men in the Multicenter AIDS Cohort Study. The median inter-scan interval was 4.5 years. Stenosis was graded as 0, 1-29, 30-49, 50-69 or ≥70%. Progression was defined as an increase ≥2 categories. Suppressed HIV infection was consistent viral loads 1 viral load >500 copies/ml demonstrated greatest stenosis progression (RR 3.01; 95% CI, 1.53-4.92, p=0.001 compared with HIV- men). Suppressed HIV+men with suboptimal antiretroviral adherence had greater stenosis progression (RR 1.91; 95% CI 1.12-3.24, p=0.02) than HIV+suppressed men with optimal adherence.ConclusionsCoronary artery stenosis progression was associated with suboptimal HIV RNA suppression and antiretroviral therapy adherence. Effective ongoing HIV virologic suppression and antiretroviral therapy adherence may mitigate risk for coronary disease events among people living with HIV.

Aims The extent to which human immunodeficiency viral (HIV) infection is independently associated with myocardial disease in the era of combination antiretroviral therapy (cART) remains understudied. We assessed differences in cardiovascular magnetic resonance imaging (CMR) metrics among people living with HIV (PLWH) and without HIV (PWOH). Methods and results Among 436 participants (aged 54.7 ± 6.0 years, 29% women) from three cohorts, we acquired CMR cines, late gadolinium enhancement (LGE), and T1 mapping. Multivariable linear regressions were used to evaluate associations between HIV serostatus and CMR metrics. Baseline characteristics were similar by HIV serostatus; 63% were PLWH of whom 88% received cART and 73% were virally suppressed. Median left ventricular ejection fraction was normal and similar by HIV serostatus (73%, PWOH vs. 72%, PLWH, P = 0.43) as were right ventricular function, biventricular volumes, and masses. LGE prevalence was similar (32%, PWOH vs. 36%, PLWH, P = 0.46) with low scar extents (4.1, PWOH vs. 4.9 g, PLWH, P = 0.51) and few ischaemic scars (3%, PWOH vs. 4%, PLWH, P = 0.70). Extracellular volume fraction (ECV) was higher among PLWH (29.2 ± 4.1% vs. 28.3 ± 3.7%, P = 0.04) as was indexed maximum left atrial (LA) volume (LAVI, 29.7 ± 10.3 vs. 27.8 ± 8.7 mL/m2, P = 0.05). After multivariate adjustment, ECV was 0.84% higher among PLWH (P = 0.05) and LAVI was 2.45 mL/m2 larger (P = 0.01). HIV seropositivity and higher ECV contributed to higher LAVI (P Conclusion HIV seropositivity was independently associated with greater diffuse non-ischaemic fibrosis and larger LA volume but no other differences in CMR metrics.

In 2019, the National Institutes of Health combined the Multicenter AIDS Cohort Study (MACS) and the Women’s Interagency HIV Study (WIHS) into the MACS/WIHS Combined Cohort Study (MWCCS). In this paper, participants who made a study visit during October 2018–September 2019 (targeted for MWCCS enrollment) are described by human immunodeficiency virus (HIV) serostatus and compared with people living with HIV (PLWH) in the United States. Participants include 2,115 women and 1,901 men with a median age of 56 years (interquartile range, 48–63); 62% are PLWH. Study sites encompass the South (18%), the Mid-Atlantic/Northeast (45%), the West Coast (22%), and the Midwest (15%). Participant race/ethnicity approximates that of PLWH throughout the United States. Longitudinal data and specimens collected for 35 years (men) and 25 years (women) were combined. Differences in data collection and coding were reviewed, and key risk factor and comorbidity data were harmonized. For example, recent use of alcohol (62%) and tobacco (28%) are common, as are dyslipidemia (64%), hypertension (56%), obesity (42%), mildly or severely impaired daily activities (31%), depressive symptoms (28%), and diabetes (22%). The MWCCS repository includes serum, plasma, peripheral blood mononuclear cells, cell pellets, urine, cervicovaginal lavage samples, oral samples, B-cell lines, stool, and semen specimens. Demographic differences between the MACS and WIHS can confound analyses by sex. The merged MWCCS is both an ongoing observational cohort study and a valuable resource for harmonized longitudinal data and specimens for HIV-related research.

Subclinical cytomegalovirus (CMV) replication is associated with strong cellular immune response and chronic inflammation, which could contribute to aging-related conditions such as cardiovascular disease and frailty. However, because of very low levels of CMV DNA present in people with chronic CMV infection, it has been difficult to explore the virologic and immunologic mechanisms of chronic low-level CMV infection and a sensitive method to monitor CMV replication is needed. Droplet digital PCR (ddPCR) has been shown to have higher precision and reproducibility than real-time quantitative PCR (qPCR) in quantifying low levels of CMV DNA, but it is not always sensitive enough for this purpose. Through rigorous validation experiments, we demonstrated that sensitivity and precision of quantification of very low levels of CMV DNA by ddPCR can be significantly increased by preamplification of samples with 10-20 cycles of conventional PCR, especially when testing CMV DNA in the presence of cellular DNA. With preamplification, we could reliably quantify down to two copies of CMV DNA, as opposed to five copies without preamplification. Further studies are needed to determine if ddPCR with preamplification can facilitate mechanistic studies of the characteristics and consequences of chronic CMV infection in aging adults.

ObjectivesWe investigated whether the effect of smoking on the incidence of smoking-related cancers differs by HIV-infection status, if sex modifies the impact of risk factors for smoking-related cancers, and the sex-specific attributable risk of smoking on cancer incidence.DesignData from two large prospective studies in the United States were analyzed: 6789 men in the Multicenter AIDS Cohort Study from 1984 through 2018 and 4423 women in the Women's Interagency HIV Study from 1994 through 2018.MethodsIncidence rates, relative risks, and adjusted population attributable fractions (PAFs) were calculated for smoking-related cancers.ResultsDuring study follow-up, there were 214 incident smoking-related cancers in the men and 192 in the women. The age-adjusted incidence ratess for smoking-related cancers were higher in the women (392/100 000) than for the men (198/100 000; P

Study Objectives Along with multiple chronic comorbidities, sleep disorders are prevalent in people living with human immunodeficiency virus (HIV) infection. The goal of this study was to establish methods for assessing sleep quality and breathing-related disorders using self-applied home polysomnography in people with and without HIV. Methods Self-applied polysomnography was conducted on 960 participants in the Multicenter AIDS Cohort Study (MACS) using the Nox A1 recorder to collect data on the frontal electroencephalogram (EEG), bilateral electrooculograms, and a frontalis electromyogram during sleep. Breathing patterns were characterized using respiratory inductance plethysmography bands and pulse oximetry. Continuous recordings of the electrocardiogram were also obtained. All studies were scored centrally for sleep stages and disordered breathing events. Results Successful home polysomnography was obtained in 807 of 960 participants on the first attempt and 44 participants on the second. Thus, a successful polysomnogram was obtained in 851 (88.6%) of the participants. Reasons for an unsuccessful study included less than 3 h of data on oximetry (34.6%), EEG (28.4%), respiratory inductance plethysmography (21.0%), or two or more of these combined (16.0%). Of the successful studies (N = 851), signal quality was rated as good, very good, or excellent in 810 (95.2%). No temporal trends in study quality were noted. Independent correlates of an unsuccessful study included black race, current smoking, and cocaine use. Conclusions Home polysomnography was successfully completed in the MACS demonstrating its feasibility in a community cohort. Given the burden of in-lab polysomnography, the methods described herein provide a cost-effective alternative for collecting sleep data in the home.

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: Extracellular vesicles (EVs) are mediators of horizontal transfer of bioactive molecules between cells and regulators of cell-cell interaction. EV-mediated cell-cell interactions play roles in physiological and pathophysiological conditions. However, the effect of pathogens and cocaine use on EV composition and function are not fully understood. Methods: We obtained 64 seminal plasma specimens from HIV-1-uninfected (HIV—and HIV-1-infected (HIV+) participants who used cocaine (COC—) or did not use cocaine (COC+). The participants were divided into 4 clinical groups (16 per group) denoted as HIV–COC–, HIV–COC+, HIV+COC–, and HIV+COC+ were used. The seminal plasma was used to isolate EVs (SEVs) by differential centrifugation and PPLC-based size exclusion chromatography (SEC) as previously described. We used the SEV to study how HIV infection and cocaine regulate the repertoire and functions of EV-associated proteins, miRNA, and their interactome. After paired proteomics and small RNA-Sequencing (sRNA-Seq) analyses, we employed an in vitro two-dimensional-substrate single cell haptotaxis assay for quantitative assessment of the effect of different SEV on monocyte haptotaxis. Finally, we functionalized SEV with exogenous miR-128 to directly address the role of SEV-associated miR-128 on monocyte haptotaxis. Findings: Systems biology and multi-omics analysis showed that HIV infection (HIV+) and cocaine (COC) use (COC+) promote the release of SEV with dysregulated extracellular proteome (exProtein), miRNAome (exmiR), and exmiR networks. Integrating SEV proteome and miRNAome revealed a significant decrease in the enrichment of disease-associated, brain-enriched, and HIV-associated miR-128-3p (miR-128) in HIV+COC+ SEV along with a concomitant increase in miR-128 targets—PEAK1 and RND3/RhoE. Two-dimensional-substrate single cell haptotaxis showed that in the presence of HIV+COC+ SEVs, contact guidance provided by the extracellular matrix (ECM, collagen type 1) network facilitated far-ranging haptotactic cues that guided monocytes over longer distances. Functionalizing SEVs with miR-128 mimic revealed that the strategic changes in monocyte haptotaxis are in large part the result of SEV-associated miR-128. Interpretation: Compositionally and functionally distinct HIV+COC+ and HIV–COC– SEVs and their exmiR networks may provide cells relevant but divergent haptotactic guidance in the absence of chemotactic cues, under both physiological and pathophysiological conditions. Funding Statement: This work was supported by grants from the National Institute on Drug Abuse (NIDA), grants DA042348, DA050169 and DA053643 to C.M.O. Declaration of Interests: None to declare. Ethics Approval Statement: This study was conducted according to University regulations approved by Stony Brook University Institutional Review Boards (IRB # 201608703) using de-identified human specimens obtained through the Multicenter AIDS Cohort Study (MACS).

Background Chronic cytomegalovirus (CMV) infection has been postulated as a driver of chronic inflammation that has been associated with frailty and other age-related conditions in both HIV-infected (HIV+) and -uninfected (HIV-) people. Methods To study the T cell response to CMV as a predictor of onset and maintenance of frailty, baseline CMV-specific T cell responses of 42 men (20 HIV-, 22 HIV+; 21 frail, 21 nonfrail) in the Multicenter AIDS Cohort Study (MACS) were assessed by flow cytometric analysis of cytokine production (IFN-γ, TNF-⍺, and IL-2) in response to overlapping peptide pools spanning 19 CMV open reading frames. The Fried frailty phenotype was assessed at baseline and semiannually thereafter. Times to transition into or out of frailty were compared by tertiles of percentages of cytokine-producing T cells using Kaplan-Meier estimators and the exact log-rank test. Results Over a median follow-up of 6.5 (interquartile range: 2) years, faster onset of frailty was significantly predicted by higher (HIV- men) or lower (HIV+ men) percentages of CD4 T cells producing only IFN-γ (IFN-γ-single-producing (SP)), and by lower percentages of IFN-γ-, TNF-⍺-, and IL-2-triple-producing CD8 T cells (HIV- men). Greater maintenance of frailty was significantly predicted by lower percentages of both these T cell subsets in HIV- men, and by lower percentages of IFN-γ-SP CD4 T cells in HIV+ men. The antigenic specificity of IFN-γ-SP CD4 T cells was different between HIV- and HIV+ nonfrail men, as were the correlations between these cells and serum inflammatory markers. Conclusions In this pilot study, percentages of CMV-specific T cells predicted the onset and maintenance of frailty in HIV- and HIV+ men. Predictive responses differed by HIV status, which may relate to differential control of CMV reactivation and inflammation by anti-CMV T cell responses.

Background Clinically useful predictors for fatal toxoplasmosis are lacking. We investigated the value of serological assays for antibodies to whole Toxoplasma antigens and to peptide antigens of the Toxoplasma cyst matrix antigen 1 (MAG1), for predicting incident toxoplasmic encephalitis (TE) in people living with human immunodeficiency virus (HIV; PLWH). Methods We performed a nested case control study, conducted within the Multicenter AIDS Cohort Study (MACS), using serum samples obtained 2 years prior to diagnosis of TE from 28 cases, and 37 HIV disease-matched Toxoplasma seropositive controls at matched time-points. Sera were tested for Toxoplasma antibodies using a commercial assay and for antibodies to MAG1_4.2 and MAG1_5.2 peptides in enzyme-linked immunosorbent assay (ELISA). Results Two years prior to clinical diagnosis, 68% of TE cases were MAG1_4.2 seropositive compared with 16% of controls (odds ratio [OR] 25.0, 95% confidence interval [CI] 3.14–199.18). Corresponding results for MAG1_5.2 seropositivity were 36% and 14% (OR 3.6, 95% CI .95–13.42). Higher levels of antibody to MAG1_4.2 (OR 18.5 per doubling of the optical density [OD] value, 95% CI 1.41–242) and to Toxoplasma (OR 2.91 for each OD unit increase, 95% CI 1.48–5.72) were also associated with the risk of TE. When seropositivity was defined as the presence of MAG1 antibody or relatively high levels of Toxoplasma antibody, the sensitivity was 89% and specificity was 68% for subsequent TE. Conclusions Antibodies to MAG1 showed predictive value on the occurrence of TE in PLWH, and the predictive performance was further improved by adding the levels of Toxoplasma antibody. These measures could be clinically useful for predicting subsequent diseases in multiple at-risk populations.

Cancer recurrence after surgery remains an unresolved clinical problem1–3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4–6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy. In mouse models of pulmonary metastasis, adjuvant epigenetic therapy targeting myeloid-derived suppressor cells disrupts the premetastatic microenvironment after resection of primary tumours and inhibits the dissemination of residual tumour cells.

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.

Clonal expansion of infected CD4(+) T cells is a major mechanism of HIV-1 persistence and a barrier to achieving a cure. Potential causes are homeostatic proliferation, effects of HIV-1 integration, and interaction with antigens. Here, we show that it is possible to link antigen responsiveness, the full proviral sequence, the integration site, and the T cell receptor β-chain (TCRβ) sequence to examine the role of recurrent antigenic exposure in maintaining the HIV-1 reservoir. We isolated CMV- and Gag-responding CD4(+) T cells from 10 treated individuals. Proviral populations in CMV-responding cells were dominated by large clones, including clones harboring replication-competent proviruses. TCRβ repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2, STAT5B, MKL1), the proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCRβ and integration site analysis showed that infection could occur early or late in the course of a clone’s response to antigen and could generate infected cell populations too large to be explained solely by homeostatic proliferation. Together, these findings implicate antigen-driven clonal selection as a major factor in HIV-1 persistence, a finding that will be a difficult challenge to eradication efforts.

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.

Both aging and treated human immunodeficiency virus (HIV) infection are characterized by low-level chronic inflammation and immune activation which contribute to the development of age-related diseases, frailty, and early mortality. Chronic cytomegalovirus (CMV) infection is highly prevalent in older adults and HIV-infected populations. A number of studies have shown that CMV induces broad and strong T-cell responses in CMV-seropositive older adults and HIV-infected individuals. CMV infection rarely develops into clinical disease in immunocompetent individuals. However, a large body of literature has shown adverse effects of chronic CMV infection on the health and longevity of these populations. It has been hypothesized that chronic CMV infection may be a driver of chronic inflammation and immune activation, and may further contribute to the development of frailty. Thus, there is a need to better understand the extent of the impact of chronic CMV infection on T-cell immunity and health in aging and HIV infection. In this review, we will address important considerations and challenges in the assessment of chronic CMV infection and CMV-specific T-cell responses. We will then review recent data on relationships between T-cell responses to CMV and levels of inflammatory markers and immune activation, as well as the onset of frailty.

Background: HIV-1 set point viral load (SPVL) is a highly variable trait that influences disease progression and transmission risk. Men who are exclusively insertive (EI) during anal intercourse require more sexual contacts to become infected than exclusively receptive (ER) men. Thus, we hypothesize that EIs are more likely to acquire their viruses from highly infectious partners (i.e., with high SPVLs) and to have higher SPVLs than infected ERs. Methods: We used a one-generation Bernoulli model, a dynamic network model, and data from the Multicenter AIDS Cohort Study (MACS) to examine whether and under what circumstances MSM differ in SPVL by sexual role. Results: Both models predicted higher SPVLs in EIs than role versatile (RV) or ER men, but only in scenarios where longer-term relationships predominated. ER and RV men displayed similar SPVLs. EI men remained far less likely than ER men to become infected, however. When the MACS data were limited by some estimates of lower sex partner counts (a proxy for longer relationships), EI men had higher SPVLs; these differences were clinically relevant (>0.3 log10 copies/mL) and statistically significant (p

ObjectiveTo determine the association of insulin sensitivity and metabolic status with declining cognition in HIV-infected individuals.MethodsWe conducted targeted clinical and metabolic measures in longitudinal plasma samples obtained from HIV-infected patients enrolled in the Central Nervous System HIV Anti-Retroviral Therapy Effects Research Study (CHARTER). Findings were validated with plasma samples from the Multicenter AIDS Cohort Study (MACS). Patients were grouped according to longitudinally and serially assessed cognitive performance as having stably normal or declining cognition.ResultsPatients with declining cognition exhibited baseline hyperinsulinemia and elevated plasma c-peptide levels with normal c-peptide/insulin ratios, suggesting that insulin production was increased, but insulin clearance was normal. The association of hyperinsulinemia with worsening cognition was further supported by low high-density lipoprotein (HDL), high low-density lipoprotein/HDL ratio, and elevated cholesterol/HDL ratio compared to patients with stably normal cognition.ConclusionsThese findings suggest that hyperinsulinemia and impaired insulin sensitivity are associated with cognitive decline in antiretroviral therapy–treated HIV-infected patients.

A stable latent reservoir for HIV-1 in resting CD4+ T cells is the principal barrier to a cure1-3. Curative strategies that target the reservoir are being tested4,5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays for cells that release infectious virus after one round of T cell activation1. However, these quantitative outgrowth assays and newer assays for cells that produce viral RNA after activation6 may underestimate the reservoir size because one round of activation does not induce all proviruses7. Many studies rely on simple assays based on polymerase chain reaction to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority of proviruses are defective7-9. Here we describe a more accurate method of measuring the HIV-1 reservoir that separately quantifies intact and defective proviruses. We show that the dynamics of cells that carry intact and defective proviruses are different in vitro and in vivo. These findings have implications for targeting the intact proviruses that are a barrier to curing HIV infection.

HIV-infected men have increased rates of osteoporosis and fracture compared to HIV-uninfected men. Testosterone use among HIV-infected men is common. In HIV-uninfected men, testosterone increases bone mineral density (BMD), but its effects have not been evaluated in HIV-infected men. In a substudy of Multicenter AIDS Cohort Study (MACS), the Bone Strength Substudy (BOSS) enrolled 202 HIV-infected and 201 HIV-uninfected men aged between 50 and 69 years. Study participants underwent dual-energy X-ray absorptiometry (DXA) at the lumbar spine (LS), total hip (TH), and femoral neck (FN) and detailed assessment of osteoporosis risk factors. We used multivariable linear regression to determine associations and 95% confidence intervals (CIs) between self-reported testosterone use and T-scores at the LS, TH, and FN after adjustment for demographics, behavioral covariates, comorbidities, and other traditional osteoporosis risk factors. HIV-infected men reported more frequent testosterone use (22% vs. 4%; p

Author(s): Bourgi, Kassem; Jenkins, Cathy A; Rebeiro, Peter F; Palella, Frank; Moore, Richard D; Altoff, Keri N; Gill, John; Rabkin, Charles S; Gange, Stephen J; Horberg, Michael A; Margolick, Joseph; Li, Jun; Wong, Cherise; Willig, Amanda; Lima, Viviane D; Crane, Heidi; Thorne, Jennifer; Silverberg, Michael; Kirk, Gregory; Mathews, William C; Sterling, Timothy R; Lake, Jordan; Koethe, John R; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) | Abstract: IntroductionWeight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio-metabolic disease. We assessed relationships between ART drug class and weight change among treatment-naive PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).MethodsAdult, treatment-naive PWH in NA-ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV-1 RNA level and CD4+ cell count. Due to shorter follow-up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with g10% weight gain at two and five years.ResultsAmong 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI-, 31% started PI- and 20% started INSTI-based regimens (1624 raltegravir (RAL), 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI-based regimens had mean estimated five-year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two-year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline CD4+ cell counts, and those initiating INSTI-based regimens had higher odds of g10% body weight increase at two years (adjusted odds ration=n1.37, 95% confidence interval: 1.20 to 1.56 vs. NNRTI).ConclusionsPWH initiating INSTI-based regimens gained, on average, more weight compared to NNRTI-based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration.

The inflammatory context of HIV infection has been posited to contribute to the higher comorbidity risk noted in HIV-infected populations. One possible pathway may involve 1,25-dihydroxyvitamin D [1,25(OH)(2)D], which plays a wide biologic role in many tissues. We sought to investigate whether inflammation was associated with vitamin D metabolites in a cohort of HIV-infected (HIV+) men receiving treatment and HIV-uninfected (HIV−) men. Vitamin D metabolites, including 25-hydroxyvitamin D [25(OH)D] and 1,25(OH)(2)D, were measured along with 24 inflammatory markers among Multicenter AIDS Cohort Study participants. Exploratory factor analysis reduced inflammatory marker data to a smaller set of inflammatory processes (IPs). Multivariate linear regression was used to evaluate associations between vitamin D metabolites and IPs. There were 466 HIV+ and 100 HIV− men, who contributed 658 stored samples from 1998 to 2008. We found three IPs with IP 1 characterized by sTNF-R2, sIL-2Rα, sCD27, BAFF, sgp130, sCD14, CXCL10 (IP-10), and sIL-6R. While none of the three IPs was associated with 25(OH)D levels in either HIV+ or HIV−, higher levels of IP 1 were significantly associated with the reduced levels of 1,25(OH)(2)D in HIV+, and a similar although nonsignificant trend was seen in HIV−. The association between 1,25(OH)(2)D and inflammation found among HIV-infected men suggests a possible mechanism whereby inflammation leads to the increased comorbidity risk noted among HIV-infected individuals.

Objective Ongoing HIV replication while receiving combination antiretroviral therapy (cART) may reduce survival. Viremia copy-years (VCY) has shown improved mortality risk prediction over single time-point viral load measures. However, the timing of a patient's viral load history most associated with later mortality has not been studied. Here we determined the optimal duration and temporality of viral load history for predicting mortality. Design Survival analysis among HIV-positive men who initiated cART in the Multicenter AIDS Cohort Study (1995-2015). Methods VCY measures were derived from area-under-the-viral load-curve. The overall VCY based upon the complete post-cART viral load history was compared with 20 VCYs derived from viral loads assessed during different shorter time periods (the most recent 1-10 years and initial 1-10 years following cART initiation) for associations with mortality. Results Each 10-fold increase in VCYs based on the most recent 3-8 years was significantly associated with 23-26% decrease in survival times, a magnitude of effect greater than that of the most recent viral load (16%). These associations were independent of CD4 cell count and single time-point viral loads. In addition, the degree of pre-cART immunodeficiency did not affect the mortality prognostic value of VCY based on viral loads in the most recent 3 years. Conversely, the overall VCY and VCYs based on viral loads immediately following cART initiation were not independent predictors of mortality. Conclusion Among cART-treated men, VCY based upon viral loads in the recent 3 years (six viral loads) has a mortality prognostic value greater than that of the overall VCY and single time-point viral loads, making the former a more feasible measure for use.

OBJECTIVE: The relationships between frailty and body composition in older adults with HIV infection are poorly understood. We sought to describe associations between frailty and measures of body composition among adult men with HIV and without HIV DESIGN/METHODS: Men with and without HIV (age 50–69 years) in the Multicenter AIDS Cohort Study (MACS) Bone Strength Substudy were included if evaluated for frailty (by Fried phenotype) and body composition (body mass index [BMI], waist circumference [WC], abdominal visceral [VAT] and subcutaneous [SAT] adipose tissue, sarcopenia, and osteopenia/osteoporosis). All participants with HIV infection were on antiretroviral therapy. Multivariate multinomial logistic regression models were used to determine associations of frailty with body composition. RESULTS: A total of 399 men, including 199 men with HIV and 200 men without HIV, both with median age 60 years, comprised our study population. Frailty prevalence was 16.0% (men with HIV) vs 8.0% (men without HIV). HIV serostatus was associated with a 2.43 times higher odds of frailty (p=0.01). Higher WC, VAT, sarcopenia, and femoral neck osteoporosis were associated with increased odds of frailty (aOR 4.18, 4.45, 4.15, and 13.6, respectively and all p 0.20). CONCLUSION: Higher abdominal obesity and sarcopenia were associated with frailty among men with and without HIV. Assessment of these body composition parameters may help detect frailty in the clinical setting.

We examined associations of 5 plasma choline metabolites with carotid plaque among 520 HIV-infected and 217 HIV-uninfected participants (112 incident plaque cases) over 7 years. After multivariable adjustment, higher gut microbiota-related metabolite trimethylamine-N-oxide (TMAO) was associated with an increased risk of carotid plaque in HIV-infected participants (risk ratio = 1.25 per standard deviation increment; 95% confidence interval, 1.05-1.50; P = .01). TMAO was positively correlated with biomarkers of monocyte activation and inflammation (sCD14, sCD163). Further adjustment for these biomarkers attenuated the association between TMAO and carotid plaque (P = .08). Among HIV-infected individuals, plasma TMAO was associated with carotid atherosclerosis progression, partially through immune activation and inflammation.

Background Chronic immune activation is a harbinger of AIDS-associated non-Hodgkin lymphoma (AIDS-NHL), yet the underlying basis is unclear. Microbial translocation, the passage of microbial components from the gastrointestinal tract into the systemic circulation, is a source of systemic immune activation in HIV infection and may be an important contributor to chronic B-cell activation and subsequent AIDS-NHL development. Method We measured biomarkers of microbial translocation including bacterial receptors/antibodies, intestinal barrier proteins, and macrophage activation-associated cytokines/chemokines, in serum from 200 HIV-infected men from the Multicenter AIDS Cohort Study prior to their AIDS-NHL diagnosis (mean = 3.9 years; SD = 1.6 years) and 200 controls. Controls were HIV-infected men who did not develop AIDS-NHL, individually matched to cases on CD4 T-cell count, prior antiretroviral drug use, and recruitment year into the cohort. Results Biomarkers of bacterial translocation and intestinal permeability were significantly increased prior to AIDS-NHL. Lipopolysaccharide-binding protein (LPB), fatty acid-binding protein 2 (FABP2), and soluble CD14 were associated with 1.6-fold, 2.9-fold, and 3.7-fold increases in AIDS-NHL risk for each unit increase on the natural log scale, respectively. Haptoglobin had a 2.1-fold increase and endotoxin-core antibody a 2.0-fold decrease risk for AIDS-NHL (fourth versus first quartile). Biomarkers of macrophage activation were significantly increased prior to AIDS-NHL: B-cell activation factor (BAFF), IL18, monocyote chemoattractant protein-1 (MCP1), tumor necrosis factor-α (TNFα), and CCL17 had 2.2-fold, 2.0-fold, 1.6-fold, 2.8-fold, and 1.7-fold increases in risk for each unit increase on the natural log scale, respectively. Conclusion These data provide evidence for microbial translocation as a cause of the systemic immune activation in chronic HIV infection preceding AIDS-NHL development.

BACKGROUND: Both aging and treated human immunodeficiency virus (HIV)-infected populations exhibit low-level chronic immune activation of unknown etiology, which correlates with morbidity and mortality. Cytomegalovirus (CMV) infection is common in both populations, but its relation to immune activation is unknown. METHODS: T cells from men who have sex with men (22 virologically suppressed HIV(+), 20 HIV(−)) were stimulated with peptides spanning 19 CMV open reading frames, and intracellular cytokine responses were assessed. Soluble and cellular inflammatory markers were assessed by multiplex electrochemiluminescence and flow cytometry, respectively. Frailty was assessed by the Fried criteria. RESULTS: All men had responses to CMV. Proportions of CMV-responsive T cells correlated strongly (r ≥ 0.6 or ≤ −0.6; P < .05) with immunologic markers, depending on donor HIV and frailty status. Markers significantly correlated in some groups after adjustment for multiple comparisons included interferon-γ, tumor necrosis factor-α, interleukin-6, and several chemokines in serum, and the proportion of activated T cells. The magnitude of the CD4 IL-2 response significantly predicted onset of frailty in HIV(−) nonfrail men, but not in HIV(+) nonfrail men. CONCLUSIONS: T-cell responses to CMV may strongly influence chronic immune activation in HIV-uninfected and virologically suppressed HIV-infected men, and may predict frailty in HIV-uninfected men.