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Background: Persons with HIV (PWH) have both more frequent depression and higher levels of plasma inflammatory biomarkers compared to persons without HIV (PWoH). Inflammation and depressive symptoms are linked, including in PWH; however, it is unclear whether these associations differ by HIV serostatus and biological sex. Methods: Six plasma inflammatory biomarkers were assessed using samples from PWH and PWoH who participated in six NIH-funded studies through the UCSD HIV Neurobehavioral Research Program (HNRP) from 2011 to 2019. Factor analysis was performed to identify intercorrelated groups of biomarkers. Factors and their components were then examined for relationships with Beck Depression Inventory-II (BDI-II) and modifying effects of sex or HIV serostatus using multivariable linear regression, adjusting for demographics, substance use diagnoses, and relevant co-morbidities. Results: Participants included 150 PWH (age = 48.3 ± 13.1 yr; 88% biologically male) and 138 PWoH (age = 46.3 ± 15.9; 56% male). Two inflammatory factors were identified: Factor 1 loaded on interleukin-6 (IL-6), C-reactive protein (CRP), and D-dimer; Factor 2 loaded on interleukin-8, chemokine C–C ligand 2 (CCL2), and chemokine C-X-C ligand 10 (CXCL10). Sex modified the effect of Factor 1 on BDI-II, with a more positive association for men than women (p = 0.04). No significant association between Factor 2 and BDI-II was found. Of the biomarkers in Factor 1, only IL-6 was significantly associated with BDI-II and was modified by sex (p = 0.003). In sex-stratified analysis, a positive association was found for men (β = 5.42; 95% confidence interval = [1.32, 9.52]) but not women (β = −3.88; 95% C.I. = [-11.02, 3.26]). No HIV-related interactions were detected. Interpretation: We identified a depression-associated inflammatory factor present in both PWH and PWoH, consistent with prior studies of PWH only. The association was driven by a correlation between IL-6 and depression exclusively in men, suggesting that the depression-inflammation link differs by sex. Future studies of depression etiology or treatment, including those on persons with HIV, should consider the impact of biological sex in both design and analysis.

Context: Brain metabolite ratios derived from magnetic resonance spectroscopy (MRS) has been used to document changes in neuronal viability, glial activation and inflammation associated with Human Immunodeficiency Virus (HIV) infection and cardiovascular disease. Aims: To determine whether brain metabolite ratios in the left anterioar insula predicts cardio-autonomic regulation indexed by the ratio of low- to high-frequency heart rate varaibility (LF:HF) after accounting for post-menopausal age, HIV and hypertensive (HTN) status. Design: Thirty women, (n=14 HIV+ and n=16 HTN+) with an average age of 54.5 (SD=6.4) years and no history of neurological disease were recruited for the study. Methods: After conventional MR imaging, single-voxel 1H-MRS (TR = 1500 msec; TE = 35 msec) was performed by using a PROBE-SV system implemented on a 3T GE Discovery MR750 scanner. Shift-selective imaging pulses for water suppression were acquired from a voxel placed in the midline of the left anterior insula with an average voxel size of 15×15×15 mm. Heart rate variability was estimated over a 7 minutes resting state scan using an MR-compatible photoplethysmogram. Statistics: A stepwise regression analysis controlling for (1) age, disease status (HIV+ and HTN+) was modelled separately for the ratio of N-acetylaspartate (NAA), Myo-inostol (mI), and Choline (Ch) to Creatine (Cr) ratios to predict LF:HF. Results: Higher ratios of NAA/Cr were associated with lower LF:HF (β= -.393, t(29)= -2.26, p= .033). Ratios of mI:Cr and Cho:Cr did not predict LF:HF. Conclusions: Decreased neuronal viability in the left anterior insula, indexed by lower NAA/Cr metabolite ratios explain a significant proportion of the variance in the skew towards sympathetic overarusal in postmenopausal women at risk for cerebrovacular disease.