CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

mitochondrial dysfunction) faster than people without HIV (PWOH) and that depression in PWH is associated with a higher burden of heteroplasmy (HP) (number of mtDNA loci with ≥2 somatic variants) across the mtDNA genome. Methods: We performed Illumina deep mtDNA sequencing on genomic DNA sampled at 2 visits 10 years apart in 92 PWH and 37 PWOH from San Diego based observational studies (mean coverage depth 3000X). Participants underwent serial neuromedical, mental health (Beck Depression Inventory-II, BDI-II), and comprehensive cognitive assessments. A BDI-II score and cognitive, apathy, affective and somatic depressive symptom scores were obtained; demographically adjusted cognitive T-scores were converted to domain deficit scores (DDS). Plasma MCP-1 was measured by immunoassay. Raw reads were mapped to revised Cambridge Reference Sequence, and HP was called at the 1-99% threshold using the GATK Mutect2 pipeline. Change in mtDNA HP burden at 10 years was compared by HIV status, adjusting for influential covariates (univariate p<0.05). Associations of HP burden at 10 years with BDI-II scores or depression (BDI-II score ≥14) were tested in backward-elimination Poisson regression models, using the Akaike Information Criterion. Results: PWH (mean age 44, 11% female, 60% aviremic, 26% depressed) had higher plasma MCP-1 and more prevalent substance use than PWOH (mean age 45, 23% female). PWH did not acquire higher HP burdens over 10 years than PWOH (adjusted beta -2.75, p=0.337 for PWH). Higher mtDNA HP at 10 years associated with more depression (adjusted beta 0.320, p<0.001), and a higher BDI-II score (beta 0.014, p<0.001, adjusting for age, sex, race, mean coverage, HIV status, hemoglobin, smoking, plasma MCP-1, substance use, tenofovir alafenamide use, ±global cognitive impairment (DDS>0.5)), with similar results in PWH. In PWH, higher HP burden was also associated with higher BDI-II-based cognitive, apathy, affective, and somatic depressive symptom scores (adjusted betas 0.024-0.056, all p-values ≤0.01). Conclusion: PWH do not accumulate HP across the mtDNA genome faster than PWOH over a decade, but higher overall mtDNA HP burden may confer increased risk for depressive symptoms and depression, regardless of HIV status. Future studies should define the mechanisms for these associations. Sociodemographics Were Stronger Classifiers of Cognitive Profiles Than Neuroimaging in HIV Raha M. Dastgheyb 1 , Sarah Cooley 2 , Alison Buchholz 3 , Kalen J. Petersen 2 , Beau Ances 2 , Leah H. Rubin 4 1 The Johns Hopkins Hospital, Baltimore, MD, USA, 2 Washington University in St Louis, St Louis, MO, USA, 3 The Johns Hopkins University School of Medicine, Baltimore, MD, USA, 4 The Johns Hopkins University, Baltimore, MD, USA Background: Despite advancements in antiretroviral therapy, cognitive issues persist in some people with HIV (PWH) and are heterogeneous in nature. Recent research has focused on identifying cognitive profiles present in PWH and identifying factors that distinguish between these profiles; however, neuroimaging metrics of brain structure and function are rarely incorporated into these analyses. Methods: We identified cognitive profiles among 225 PWH (mean age=51; 21% female, 67% African American/Black; mean years of education=13.3 ) from a single site (Washington University in St. Louis). Participants completed a standard neuropsychological test (NP) battery of 10 tests (16 outcomes) and magnetic resonance imaging (MRI), including structural MRI to measure regional volumes and resting-state functional MRI to assess brain connectivity. Raw NP test scores were converted to scaled scores and then Kohonen self organizing maps were used to classify individuals with similar cognitive profiles. Socio-demographic features (including age, race, education, premorbid IQ (WRAT-3), and area deprivation index), HIV clinical factors (nadir and recent CD4 count, recent CD8 count, CD4/CD8 ratio, viral load), hepatitis C co-infection, depression, early life stress, brain volumes, and intra-network resting state values were compared between profiles using random forest models. Distinguishing variables were considered significant at P<0.001. Results: Five cognitive profiles were identified: 1) strength in learning and memory (n=41; 18%), 2) weakness in motor and processing speed (n=35; 15%), 3) impaired globally (n=18; 8%), 4) average globally (n=74; 33%-referent group), and 5) strong globally (n=57; 25%)(Figure 1). Compared to profile 4, profile 1 (relative strength in learning and memory) had a higher premorbid IQ; profile 3 (impaired globally) was older, less educated, and had a lower premorbid IQ; and profile 5 (strong globally) was more highly educated, had a higher premorbid IQ, and was less likely to be Black. Although several

vs 0.107/seq, p=0.046), and nucleotide substitution rate (5.53e-3 vs 1.07e-2 sub/site/year, p=0.017) when compared to those from paired CSF. Pervasive recombination was observed across env in plasma-derived variants. The ratio of recombination to point mutation (ρ/θ) was estimated to be 13.86±0.78. The ratio of nonsynonymous to synonymous substitution rate (dN/dS) was estimated to be 0.667±0.042 and 0.813± 0.044 in CSF and plasma subgroups, respectively, indicating stronger positive selection on env in plasma compared to CSF (p=0.001). Conclusion: These findings revealed distinct intra-participant HIV-1 evolutionary dynamics between the CSF and plasma and suggest stronger immune selection on HIV-1 env in the peripheral blood than in the CSF. They also suggest that on average, recombination plays a larger role in HIV-1 env diversification in the plasma than in the CSF, and is the main driver of viral adaptive evolution in the plasma in this cohort with high rates of compartmentalized virus. Effects of Recent Air Pollution Exposure on Cognition, Inflammation, and Neurodegeneration in HIV Sarah Cooley 1 , Julie Wisch 1 , Tricia Burdo 2 , Dianne Langford 2 , Rajan Chakrabarty 1 , Payton Beeler 1 , Beau Ances 1 1 Washington University in St Louis, St Louis, MO, USA, 2 Temple University, Philadelphia, PA, USA Background: Ambient air pollution, even within permissible levels, has been associated with greater risk of illness and mortality in the general population. People with HIV (PWH) may be more vulnerable to worsening climate- and pollution-associated outcomes. This study examined the association among common air pollutants on cognition and plasma biomarkers of inflammation and neurodegeneration in a cohort of community-dwelling PWH in the greater St. Louis, Missouri region. Methods: 277 PWH (43% female) and 107 people without HIV (PWoH) (26% female) from the St. Louis region completed a comprehensive cognitive battery and a blood draw. Participant addresses were used to determine census tract-based location. Spatial interpolation was applied to publicly available EPA pollution monitoring data to calculate average exposure to pollutants (fine particulate matter (PM) 2.5, PM10, ozone, lead (Pb)) in the week prior to study visit. Average PM2.5 exposure over the past calendar year was also available for a subset of participants, using NASA satellite data. Pollution data were compared with cognition and plasma markers (sCD14, sCD163, CD14CD16 monocytes, neurofilament light protein (NfL), glial fibrillary acidic protein (GFAP)) using regression models. Results: PWH and PWoH did not differ with regards to recent air pollutant exposure. Higher recent exposures to PM2.5, PM10, and Pb were associated with worse learning, delayed recall, executive functioning, and global cognition in both groups (p-values <.05). Within PWH, higher year's average PM2.5 exposure was associated with worse learning (p=.01), delayed recall (p=.02), executive functioning (p=.004), and global cognition (p<.001). Higher levels of plasma sCD163 and sCD14 positively associated with recent ozone exposure and PM2.5 in PWH (p-values <.05). Lower percentages of classical monocytes, and corresponding higher percentages of non-classical monocytes, were associated with higher PM2.5 in PWH (p=.001). Higher PM10 and ozone exposure was associated with higher NfL and GFAP in both groups (p-values <.01). Conclusion: Recent exposures to common air pollutants were associated with poorer outcomes in cognition, inflammatory markers and monocytes, and markers of neurodegeneration in PWoH and PWH. Increases in ambient air pollution may trigger an immune response, particularly in PWH, that then may contribute to neurodegeneration and worse cognitive performance. However, longitudinal studies of air pollution with regards to these measures are needed in PWH. Higher Mitochondrial DNA (mtDNA) Heteroplasmy Burden Associates With Depression in People With HIV Emmanuel Saake 1 , Chunyu Liu 1 , Kavita Sharma 2 , Donald Franklin 3 , Todd Hulgan 4 , David C. Samuels 4 , Robert K. Heaton 3 , Scott L. Letendre 5 , Ronald J. Ellis 5 , Asha R Kallianpur 2 1 Boston University, Boston, MA, USA, 2 Cleveland Clinic, Cleveland, OH, USA, 3 University of California San Diego, La Jolla, CA, USA, 4 Vanderbilt University, Nashville, TN, USA, 5 University of California San Diego, San Diego, CA, USA Background: Depression is extremely common in people with HIV (PWH) and may involve immunometabolic dysfunction via mTOR hyperactivation. We tested the hypotheses that PWH acquire somatic mtDNA variants (linked to

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