Loss of gut mucosal integrity and an aberrant gut microbiota are proposed mechanisms contributing to chronic inflammation and increased morbidity and mortality during antiretroviral-treated HIV disease. Sexual practice has recently been uncovered as a major source of microbiota variation, potentially confounding prior observations of gut microbiota alterations among persons with HIV (PWH). To overcome this and other confounding factors, we examine a well-powered subset of AGEhIV Cohort participants comprising antiretroviral-treated PWH and seronegative controls matched for age, body-mass index, sex, and sexual practice. We report significant gut microbiota differences in PWH regardless of sex and sexual practice including Gammaproteobacteria enrichment, Lachnospiraceae and Ruminococcaceae depletion, and decreased alpha diversity. Men who have sex with men (MSM) exhibit a distinct microbiota signature characterized by Prevotella enrichment and increased alpha diversity, which is linked with receptive anal intercourse in both males and females. Finally, the HIV-associated microbiota signature correlates with inflammatory markers including suPAR, nadir CD4 count, and prevalence of age-associated noncommunicable comorbidities.

Background Frailty is associated with mortality and morbidity in the general geriatric population, but less is known about its impact among the aging but generally younger population with human immunodeficiency virus (HIV). Methods The impact of frailty on all-cause mortality during 6 years of follow-up and incident comorbidity during 4 years of follow-up was assessed among 598 HIV-positive and 550 comparable HIV-negative participants aged ≥ 45 years of the AGEhIV Cohort Study. Frailty encompasses 5 domains; weight loss, low physical activity, exhaustion, decreased grip strength, and slow gait speed. Presence of ≥ 3 denotes frailty, 1–2 prefrailty, and 0 robust. Multivariable Cox and logistic regression models were used to assess the independent relationships of frailty with both outcomes, adjusting for HIV infection and traditional risk factors. Results At baseline, 7.5% (n = 86) of participants were frail. During follow-up, 38 participants died. Mortality rate was significantly higher among frail participants: 25.7/1000 person-years of follow-up (PYFU) (95% confidence interval [CI], 14.2–46.4) compared with prefrail (7.2/1000 PYFU [95% CI, 4.7–11.2]) and robust (2.3/1000 PYFU [95% CI, 1.1–4.9]). In fully adjusted analyses, frailty remained strongly associated with death (hazard ratio, 4.6 [95% CI, 1.7–12.5]) and incident comorbidity (odds ratio, 1.9 [95% CI, 1.1–3.1]). No interactions were observed between frailty and HIV status in all analyses. Conclusions Frailty is a strong predictor of both mortality and incident comorbidity independent from other risk factors. Clinical Trials Registration NCT01466582.

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BackgroundThe AGE h IV cohort study is a prospective cohort study evaluating the occurrence of age-related comorbidities in people living with and without HIV. We previously reported a lower forced vital capacity (FVC) in HIV-positive compared with HIV-negative participants in those without heavy smoking exposure at time of enrolment in the AGE h IV cohort study. In this study we evaluate longitudinal changes in spirometry indices in the same AGE h IV cohort accounting for smoking behaviour and other risk factors.Methods We obtained pre-bronchodilator spirometry measurements in AGE h IV cohort participants during biennial visits over a median of 5•9 years (IQR 5•7-6•0). Adjusted declines in forced expiratory volume in 1 s (FEV 1 ), FVC, and FEV 1 /FVC ratio were modelled using linear mixed-effects models and compared by HIV status and smoking status. To evaluate whether changes in spirometry measurements could be driven by increased levels of chronic inflammation, we assessed associations between rates of FEV 1 and FVC decline and CD4 and CD8 T-cell counts, and plasma concentrations of C-reactive protein (CRP), interleukin 6, soluble CD14, soluble CD163, and intestinal fatty-acidbinding protein in separate models. The study is registered at ClinicalTrials.gov, NCT01466582.Findings 500 HIV-positive and 481 HIV-negative participants were included with spirometry data from Oct 29, 2010, to Aug 14, 2018. HIV-positive participants were virally suppressed (<40 copies per mL) during 1627 (95%) study visits, and 159 (32%) HIV-positive and 183 (38%) HIV-negative participants had never smoked. Adjusted declines in FEV 1 were 10•0 mL per year faster in HIV-positive non-smokers (95% CI 4•2 to 15•7, p=0•00066) compared with HIV-negative non-smokers, and 11•1 mL per year faster in HIV-positive smokers (95% CI 0•7 to 21•4, p=0•036) compared with HIV-negative smokers. In comparison, smoking was associated with a 16•4 mL per year steeper decline in FEV 1 among HIV-positive participants (95% CI 8•0 to 24•7, p=0•00012), and 15•3 mL per year steeper decline among HIV-negative participants (95% CI 6•7-24•0, p=0•00052) compared with not smoking. Adjusted yearly declines in FEV₁ and FVC, but not FEV₁/FVC, were significantly greater in HIV-positive than HIVnegative participants overall (additional decline in HIV-positive participants, FEV₁ 10•5 mL per year [95% CI 4•7 to 16•3], p=0•00040; FVC 11•5 mL per year [2•8 to 20•3], p=0•0096; FEV₁/FVC 0•07% per year [-0•05 to 0•19], p=0•26), with a similar observation for never-smokers (FEV₁ 6•0 mL per year [-1•8 to 13•7], p=0•13; FVC 9•1 mL per year [-3•0 to 21•1], p=0•14; FEV 1 /FVC ratio 0•00% per year [-0•18 to -0•18], p=0•97). Higher CRP concentrations during follow-up were associated with accelerated declines in FEV 1 and FVC among HIV-positive participants but not among HIV-negative participants.Interpretation Treated HIV infection was associated with faster declines in both FEV 1 and FVC, but not in the FEV 1 /FVC ratio. These changes were independent of smoking and might have been drive...

X-linked adrenoleukodystrophy (ALD) is a severe neurodegenerative disorder caused by the accumulation of very long-chain fatty acids (VLCFA) due to mutations in the ABCD1 gene. The phenotypic spectrum ranges from a fatal cerebral demyelinating disease in childhood (cerebral ALD) to a progressive myelopathy without cerebral involvement in adulthood (adrenomyeloneuropathy). Because ABCD1 mutations have no predictive value with respect to clinical outcome a role for modifier genes was postulated. We report that the CYP4F2 polymorphism rs2108622 increases the risk of developing cerebral ALD in Caucasian patients. The rs2108622 polymorphism (c.1297G>A) results in an amino acid substitution valine for methionine at position 433 (p.V433M). Using cellular models of VLCFA accumulation, we show that p.V433M decreases the conversion of VLCFA into very long-chain dicarboxylic acids by ω-oxidation, a potential escape route for the deficient peroxisomal β-oxidation of VLCFA in ALD. Although p.V433M does not affect the catalytic activity of CYP4F2 it reduces CYP4F2 protein levels markedly. These findings open perspectives for therapeutic interventions in a disease with currently limited treatment options.

Unbiased plasma proteomics in a matched case-control study of treated people with HIV (PWH) revealed the complement cascade as being among the top pathways enriched in PWH. Specific complement components, namely C5, associated significantly with non-AIDS comorbidity prevalence, and did so more strongly than previously established predictive biomarkers.

Background We previously reported T-cell senescence to be similar in people with human immunodeficiency virus (PWH) with suppressed viremia (predominantly men who have sex with men [MSM]) and human immunodeficiency virus (HIV)-negative otherwise comparable controls but greater than in healthy blood donors. This led us to compare CD4+ and CD8+ T-cell counts and CD4+/CD8+ ratios between HIV-negative MSM and men who only have sex with women (MSW) and relate observed differences in behavioral factors and infectious exposures, including cytomegalovirus (CMV) infection. Methods In 368 HIV-negative MSM and 72 HIV-negative MSW, T lymphocyte phenotyping was performed 3 times biennially. Baseline CMV serology and sexually transmitted infection (STI) incidence and/or STI seroprevalence, sexual, and substance-use behavior data were collected during study visits. Results Men who have sex with men, compared with MSW, had higher CD8+ counts (551 vs 437 cells/mm3, P &lt; .001), similar CD4+ counts (864 vs 880 cells/mm3, P = .5), and lower CD4+/CD8+ ratios (1.84 vs 2.47, P &lt; .001). Differences were most pronounced for MSM with &gt;10 recent sex partners and partly explained by higher CMV seroprevalence in MSM. Conclusions These findings suggest that factors other than HIV may, in both PWH and certain HIV-negative MSM, contribute to a low CD4+/CD8+ ratio. Whether this, like in PWH, contributes to comorbidity risk in HIV-negative MSM requires further study.

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