Publications by authors named "Ronald J Ellis"

254 Publications

Reduced gut microbiome diversity in people with HIV who have distal neuropathic pain.

J Pain 2021 Sep 13. Epub 2021 Sep 13.

Department of Pediatrics, University of California, San Diego.

Objective: . Gut dysbiosis, defined as pathogenic alterations in the distribution and abundance of different microbial species, is associated with neuropathic pain in a variety of clinical conditions, but this has not been explored in the context of neuropathy in people with HIV (PWH).

Methods: . We assessed gut microbial diversity and dysbiosis in PWH and people without HIV (PWoH), some of whom reported distal neuropathic pain (DNP). DNP was graded on a standardized, validated severity scale. The gut microbiome was characterized using 16S rRNA sequencing and diversity was assessed using phylogenetic tree construction. Songbird analysis (https://github.com/mortonjt/songbird) was used to produce a multinomial regression model predicting counts of specific microbial taxa through metadata covariate columns.

Results: . Participants were 226 PWH and 101 PWoH, mean (SD) age 52.0 (13.5), 21.1% female, 54.7% men who have sex with men (MSM), 44.7% non-white. Among PWH, median (interquartile range, IQR) nadir and current CD4 were 174 (21, 302) and 618 (448, 822) respectively; 90% were virally suppressed on antiretroviral therapy. PWH and PWoH did not differ with respect to microbiome diversity as indexed by Faith's phylogenetic diversity (PD). More severe DNP was associated with lower alpha diversity as indexed by Faith's PD in PWH (Spearman's ρ = 0.224, p = 0.0007), but not in PWoH (Spearman's ρ = 0.032, p = 0.748). These relationships were not confounded by demographics or disease factors. In addition, the log-ratio of features identified at the genus level as Blautia to Lachnospira was statistically significantly higher in PWH with DNP than in PWH without DNP (t-test, p = 1.01e-3). Furthermore, the log-ratio of Clostridium features to Lachnospira features also was higher in PWH with DNP than in those without (t-test, p = 6.24e-5) CONCLUSIONS: . Our results, in combination with previous findings in other neuropathic pain conditions, suggest that gut dysbiosis, particularly reductions in diversity and relative increases in the ratios of Blautia and Clostridium to Lachnospira, may contribute to prevalent DNP in PWH. Two candidate pathways for these associations, involving microbial pro-inflammatory components and microbially-produced anti-inflammatory short chain fatty acids, are discussed. Future studies might test interventions to re-establish a healthy gut microbiota and determine if this prevents or improves DNP.
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http://dx.doi.org/10.1016/j.jpain.2021.08.006DOI Listing
September 2021

Cannabis and Inflammation in HIV: A Review of Human and Animal Studies.

Viruses 2021 Aug 2;13(8). Epub 2021 Aug 2.

Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Road, La Jolla, CA 92037, USA.

Persistent inflammation occurs in people with HIV (PWH) and has many downstream adverse effects including myocardial infarction, neurocognitive impairment and death. Because the proportion of people with HIV who use cannabis is high and cannabis may be anti-inflammatory, it is important to characterize the impact of cannabis use on inflammation specifically in PWH. We performed a selective, non-exhaustive review of the literature on the effects of cannabis on inflammation in PWH. Research in this area suggests that cannabinoids are anti-inflammatory in the setting of HIV. Anti-inflammatory actions are mediated in many cases through effects on the endocannabinoid system (ECS) in the gut, and through stabilization of gut-blood barrier integrity. Cannabidiol may be particularly important as an anti-inflammatory cannabinoid. Cannabis may provide a beneficial intervention to reduce morbidity related to inflammation in PWH.
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http://dx.doi.org/10.3390/v13081521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402692PMC
August 2021

Current Considerations for Clinical Management and Care of People with HIV: Findings from the 11th Annual International HIV and Aging Workshop.

AIDS Res Hum Retroviruses 2021 Sep 20. Epub 2021 Sep 20.

Department of Psychiatry, University of California San Diego, La Jolla, California, USA.

The number of people with HIV (PWH) aged 50 years or older continues to steadily increase. The convergence of age- and HIV-related complications in these individuals presents a challenge for both patients and clinicians alike. New findings continue to emerge, as numerous researchers evaluate the combined impact of these two factors on quality of life, physiological systems, and mental health in PWH. Since its first occurrence in 2009, the International Workshop on HIV and Aging has served as a multidisciplinary meeting to share basic biomedical data, clinical trial results, treatment strategies, and epidemiological recommendations, toward better understanding and outcomes among like-minded scientific professionals. In this article, we share a selection of key findings presented in plenary talks at the 11th Annual International Workshop on HIV and Aging, held virtually from September 30, 2020 to October 2, 2020. We will also address the future directions of HIV and aging research, to further assess how the aging process intersects with chronic HIV.
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http://dx.doi.org/10.1089/AID.2021.0059DOI Listing
September 2021

Baseline Neurocognitive Impairment (NCI) Is Associated With Incident Frailty but Baseline Frailty Does Not Predict Incident NCI in Older Persons With Human Immunodeficiency Virus (HIV).

Clin Infect Dis 2021 08;73(4):680-688

University of Colorado- Anschutz Medical Campus, Aurora, Colorado, USA.

Background: Neurocognitive impairment (NCI) and frailty are more prevalent among persons with human immunodeficiency virus (HIV, PWH) compared to those without HIV. Frailty and NCI often overlap with one another. Whether frailty precedes declines in neurocognitive function among PWH or vice versa has not been well established.

Methods: AIDS Clinical Trials Group (ACTG) A5322 is an observational cohort study of older PWH. Participants undergo annual assessments for NCI and frailty. ACTG A5322 participants who developed NCI as indexed by tests of impaired executive functioning and processing speed during the first 3 years were compared to persons who maintained normal cognitive function; those who demonstrated resolution of NCI were compared to those who had persistent NCI. Participants were similarly compared by frailty trajectory. We fit multinomial logistic regression models to assess associations between baseline covariates (including NCI) and frailty, and associations between baseline covariates (including frailty) and NCI.

Results: In total, 929 participants were included with a median age of 51 years (interquartile range [IQR] 46-56). At study entry, 16% had NCI, and 6% were frail. Over 3 years, 6% of participants developed NCI; 5% developed frailty. NCI was associated with development of frailty (odds ratio [OR] = 2.06; 95% confidence interval [CI] = .94, 4.48; P = .07). Further adjustment for confounding strengthened this association (OR = 2.79; 95% CI = 1.21, 6.43; P = .02). Baseline frailty however was not associated with NCI development.

Conclusions: NCI was associated with increased risk of frailty, but frailty was not associated with development of NCI. These findings suggest that the presence of NCI in PWH should prompt monitoring for the development of frailty and interventions to prevent frailty in this population.
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http://dx.doi.org/10.1093/cid/ciab122DOI Listing
August 2021

Higher comorbidity burden predicts worsening neurocognitive trajectories in people with HIV.

Clin Infect Dis 2021 Jul 30. Epub 2021 Jul 30.

Department of Psychiatry, University of California, San Diego, UCSD HNRC, San Diego, CA, United States.

Background: Age-related comorbidities accumulate faster in people with HIV (PWH) than in those without (PWoH). We evaluated whether a validated multimorbidity scale, the Charlson Index, predicted neurocognitive trajectories in PWH.

Methods: Scaled scores a comprehensive neuropsychological battery were averaged across all visits. Multilevel modeling examined between- and within-person predictors of global neurocognition. At the between-person level, averaged Charlson scores were examined as a predictor of neurocognitive change rate, covarying for HIV disease characteristics. Within-persons, visit-specific Charlson Index was used to predict fluctuations in global neurocognition at the same and next visit, covarying for disease measures.

Results: Participants were 1195 PWH (mean baseline age 43·0; SD 9·7 years) followed for a mean of 7·1 years (range 0·5-20·5). At the between-person level, more rapid neurocognitive worsening correlated with higher (worse) average Charlson scores (standardized β -0·062, SE 0·015; p=0·001) and lower CD4 nadir (standardized β 0·055, SE 0·021; p=0·011), but not viral suppression or average CD4+ lymphocytes (ps > 0·05). At the within-person level, poorer visit-specific neurocognition was related to worse concurrent, but not preceding, Charlson scores (standardized β-0·046, SE 0·015; p = 0·003), detectable HIV viral load (standardized β0·018, SE 0·006; p = 0·001) and higher CD4+ (standardized β0·043, SE 0·009; p < 0·001).

Conclusion: The impact of comorbidities on neurocognitive decline exceeded that of HIV disease factors. Although correlative, the temporal relationships suggested that treatment of comorbidities might improve neurocognitive prognosis for PWH.
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http://dx.doi.org/10.1093/cid/ciab655DOI Listing
July 2021

Daily Cannabis Use is Associated With Lower CNS Inflammation in People With HIV.

J Int Neuropsychol Soc 2021 07;27(6):661-672

Department of Psychiatry, University of California, San Diego, USA.

Objective: Recent cannabis exposure has been associated with lower rates of neurocognitive impairment in people with HIV (PWH). Cannabis's anti-inflammatory properties may underlie this relationship by reducing chronic neuroinflammation in PWH. This study examined relations between cannabis use and inflammatory biomarkers in cerebrospinal fluid (CSF) and plasma, and cognitive correlates of these biomarkers within a community-based sample of PWH.

Methods: 263 individuals were categorized into four groups: HIV- non-cannabis users (n = 65), HIV+ non-cannabis users (n = 105), HIV+ moderate cannabis users (n = 62), and HIV+ daily cannabis users (n = 31). Differences in pro-inflammatory biomarkers (IL-6, MCP-1/CCL2, IP-10/CXCL10, sCD14, sTNFR-II, TNF-α) by study group were determined by Kruskal-Wallis tests. Multivariable linear regressions examined relationships between biomarkers and seven cognitive domains, adjusting for age, sex/gender, race, education, and current CD4 count.

Results: HIV+ daily cannabis users showed lower MCP-1 and IP-10 levels in CSF compared to HIV+ non-cannabis users (p = .015; p = .039) and were similar to HIV- non-cannabis users. Plasma biomarkers showed no differences by cannabis use. Among PWH, lower CSF MCP-1 and lower CSF IP-10 were associated with better learning performance (all ps < .05).

Conclusions: Current daily cannabis use was associated with lower levels of pro-inflammatory chemokines implicated in HIV pathogenesis and these chemokines were linked to the cognitive domain of learning which is commonly impaired in PWH. Cannabinoid-related reductions of MCP-1 and IP-10, if confirmed, suggest a role for medicinal cannabis in the mitigation of persistent inflammation and cognitive impacts of HIV.
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http://dx.doi.org/10.1017/S1355617720001447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288448PMC
July 2021

Alterations of Brain Metabolites in Adults With HIV: A Systematic Meta-analysis of Magnetic Resonance Spectroscopy Studies.

Neurology 2021 Sep 12;97(11):e1085-e1096. Epub 2021 Jul 12.

From the Department of Neuroscience (S.D., N.K., X.J.) and Department of Neurology (J.W.V.), Georgetown University Medical Center, Washington, DC; Department of Psychiatry (D.J.M., R.J.E.) and Department of Neurosciences (R.J.E.), University of California, San Diego, La Jolla.

Objective: A meta-analysis of proton magnetic resonance spectroscopy studies to investigate alterations in brain metabolites in people with HIV (PWH), the relationship between metabolite alterations and combination antiretroviral therapy (cART), and the relationship between metabolite alterations and cognitive impairment.

Methods: The PubMed database was searched for studies published from 1997 to 2020. Twenty-seven studies were identified, which included 1255 PWH and 633 controls. Four metabolites (N-acetyl aspartate [NAA], myo-inositol [mI], choline [Cho], and glutamatergic metabolites [Glx]) from 5 brain regions (basal ganglia [BG], frontal gray and white matter [FGM and FWM], and parietal gray and white matter [PGM and PWM]) were pooled separately using random-effects meta-analysis.

Results: During early HIV infection, metabolite alterations were largely limited to the BG, including Cho elevation, a marker of inflammation. cART led to global mI and Cho normalization (i.e., less elevations), but improvement in NAA was negligible. In chronic PWH on cART, there were consistent NAA reductions across brain regions, along with Cho and mI elevations in the FWM and BG, and Glx elevations in the FWM. Cognitive impairment was associated with NAA reduction and to a lesser degree mI elevation.

Conclusions: The BG are the primary region affected during early infection. cART is successful in partially controlling neuroinflammation (global mI and Cho normalization). However, neuronal dysfunction (NAA reductions) and neuroinflammation (mI and Cho elevations) persist and contribute to cognitive impairment in chronic PWH. Novel compounds targeting NAA signal pathways, along with better neuroinflammation control, may help to reduce cognitive impairment in PWH.
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http://dx.doi.org/10.1212/WNL.0000000000012394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456358PMC
September 2021

Characterization of HIV-Associated Neurocognitive Impairment in Middle-Aged and Older Persons With HIV in Lima, Peru.

Front Neurol 2021 17;12:629257. Epub 2021 Jun 17.

Facultad de Salud Pública, Universidad Peruana Cayetano Heredia, Lima, Peru.

With widespread use of antiretroviral medications, people living with HIV (PWH) are living longer worldwide, increasing their risk of developing neurocognitive impairment (NCI). The proportion of Peruvians over age 60 is expected to increase to 25% of the population by 2050, including PWH. Therefore, the problem of aging and NCI, especially in the setting of HIV infection, is uniquely pressing. We sought to study the rates of and risk factors associated with NCI among middle-aged and older PWH in Lima, Peru. Sociodemographic, medical (infectious and non-infectious), and psychiatric comorbidity and laboratory data were collected. We administered a brief neuropsychological battery evaluating seven cognitive domains affected in HIV-associated NCI and a depression screening. Cognitive test raw scores were converted to -scores that were demographically adjusted. Descriptive statistics were performed together with regression (unadjusted and adjusted) analyses to determine potential risk factors for NCI among PWH. This was a cross-sectional study in which 144 PWH aged ≥40 years attending a large HIV clinic in Lima, Peru, were recruited from September 2019 to March 2020. Mean age was 51.6 ± 7.7 years, and mean years of education were 14.0 ± 3.1 with 15% females. Median [interquartile range (IQR)] current CD4 and nadir CD4 were 554 (371, 723) and 179 (83, 291), respectively, and 10% currently had AIDS. The prevalence of NCI was 28.5%, and many demonstrated difficulty with attention and working memory (70%). One-quarter of PWH had mild depression or worse on Patient Health Questionnaire 9 (PHQ-9 ≥ 5). In bivariate analyses, neither a depression history nor a higher PHQ-9 score correlated with NCI. No other non-communicable medical or psychiatric comorbidity nor HIV characteristic was predictive of NCI. Having a positive lifetime history of hepatitis B infection, pulmonary tuberculosis, or syphilis increased risk of NCI (PR 1.72; 95% CI 1.04-2.86) in unadjusted analyses, but not in adjusted analyses. NCI among older Peruvians with HIV was found to be highly prevalent with levels consistent with prior reports of HIV-associated NCI worldwide. Common latent HIV-associated co-infections, including latent syphilis, hepatitis B infection, or pulmonary tuberculosis, may increase the risk of NCI among middle-aged and older PWH in Peru.
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http://dx.doi.org/10.3389/fneur.2021.629257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248346PMC
June 2021

Connectome-based prediction of global cognitive performance in people with HIV.

Neuroimage Clin 2021 18;30:102677. Epub 2021 Apr 18.

Departments of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, United States.

Global cognitive performance plays an important role in the diagnosis of HIV-associated neurocognitive disorders (HAND), yet to date, there is no simple way to measure global cognitive performance in people with HIV (PWH). Here, we performed connectome-based predictive modeling (CPM) to pursue a neural biomarker of global cognitive performance in PWH based on whole-brain resting-state functional connectivity. We built a CPM model that successfully predicted individual differences in global cognitive performance in the training set of 67 PWH by using leave-one-out cross-validation. This model generalized to both 33 novel PWH in the testing set and a subset of 39 PWH who completed a follow-up visit two years later. Furthermore, network strengths identified by the CPM model were significantly different between PWH with HAND and without HAND. Together, these results demonstrate that whole-brain functional network strengths could serve as a potential neural biomarker of global cognitive performance in PWH.
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http://dx.doi.org/10.1016/j.nicl.2021.102677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102633PMC
July 2021

Prevention of HIV-1 TAT Protein-Induced Peripheral Neuropathy and Mitochondrial Disruption by the Antimuscarinic Pirenzepine.

Front Neurol 2021 15;12:663373. Epub 2021 Jun 15.

Department of Psychiatry, University of California, San Diego, La Jolla, CA, United States.

HIV-associated distal sensory polyneuropathy (HIV-DSP) affects about one third of people with HIV and is characterized by distal degeneration of axons. The pathogenesis of HIV-DSP is not known and there is currently no FDA-approved treatment. HIV trans-activator of transcription (TAT) is associated with mitochondrial dysfunction and neurotoxicity in the brain and may play a role in the pathogenesis of HIV-DSP. In the present study, we measured indices of peripheral neuropathy in the doxycycline (DOX)-inducible HIV-TAT (iTAT) transgenic mouse and investigated the therapeutic efficacy of a selective muscarinic subtype-1 receptor (MR) antagonist, pirenzepine (PZ). PZ was selected as we have previously shown that it prevents and/or reverses indices of peripheral neuropathy in multiple disease models. DOX alone induced weight loss, tactile allodynia and paw thermal hypoalgesia in normal C57Bl/6J mice. Conduction velocity of large motor fibers, density of small sensory nerve fibers in the cornea and expression of mitochondria-associated proteins in sciatic nerve were unaffected by DOX in normal mice, whereas these parameters were disrupted when DOX was given to iTAT mice to induce TAT expression. Daily injection of PZ (10 mg/kg s.c.) prevented all of the disorders associated with TAT expression. These studies demonstrate that TAT expression disrupts mitochondria and induces indices of sensory and motor peripheral neuropathy and that MR antagonism may be a viable treatment for HIV-DSP. However, some indices of neuropathy in the DOX-inducible TAT transgenic mouse model can be ascribed to DOX treatment rather than TAT expression and data obtained from animal models in which gene expression is modified by DOX should be accompanied by appropriate controls and treated with due caution.
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http://dx.doi.org/10.3389/fneur.2021.663373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239242PMC
June 2021

Higher CSF Ferritin Heavy-Chain (Fth1) and Transferrin Predict Better Neurocognitive Performance in People with HIV.

Mol Neurobiol 2021 Jun 30. Epub 2021 Jun 30.

Genomic Medicine Institute, Cleveland Clinic/Lerner Research Institute, 9500 Euclid Ave/Mail Code R4-008, Cleveland, OH, 44195, USA.

HIV-associated neurocognitive disorder (HAND) remains prevalent despite antiretroviral therapy and involves white matter damage in the brain. Although iron is essential for myelination and myelin maintenance/repair, its role in HAND is largely unexplored. We tested the hypotheses that cerebrospinal fluid (CSF) heavy-chain ferritin (Fth1) and transferrin, proteins integral to iron delivery and myelination, are associated with neurocognitive performance in people with HIV (PWH). Fth1, transferrin, and the pro-inflammatory cytokines TNF-α and IL-6 were quantified in CSF at baseline (entry) in 403 PWH from a prospective observational study who underwent serial, comprehensive neurocognitive assessments. Associations of Fth1 and transferrin with Global Deficit Score (GDS)-defined neurocognitive performance at baseline and 30-42 months of follow-up were evaluated by multivariable regression. While not associated with neurocognitive performance at baseline, higher baseline CSF Fth1 predicted significantly better neurocognitive performance over 30 months in all PWH (p < 0.05), in PWH aged < 50 at 30, 36, and 42 months (all p < 0.05), and in virally suppressed PWH at all three visit time-points (all p < 0.01). Higher CSF transferrin was associated with superior neurocognitive performance at all visits, primarily in viremic individuals (all p < 0.05). All associations persisted after adjustment for neuro-inflammation. In summary, higher CSF Fth1 is neuroprotective over prolonged follow-up in all and virally suppressed PWH, while higher CSF transferrin may be most neuroprotective during viremia. We speculate that higher CSF levels of these critical iron-delivery proteins support improved myelination and consequently, neurocognitive performance in PWH, providing a rationale for investigating their role in interventions to prevent and/or treat HAND.
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http://dx.doi.org/10.1007/s12035-021-02433-7DOI Listing
June 2021

Depression is associated with hippocampal volume loss in adults with HIV.

Hum Brain Mapp 2021 Aug 5;42(12):3750-3759. Epub 2021 Jun 5.

Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, USA.

Depressive symptoms are more prevalent in persons with HIV (PWH) than HIV-uninfected individuals. In HIV-uninfected individuals, depression has been associated with atrophy in the hippocampus and other brain regions. In the present study, we investigated the impact of depression on brain structure in PWH. One hundred PWH participated in a cross-sectional study (56.6 ± 6.4 yrs, range 41-70 yrs, 24 females, 63 African Americans). The Beck's Depression Inventory-II (BDI-II) was used to assess depressive symptoms. Structural MRI images were collected. Both the voxel-based morphometry (VBM) technique and a region of interest (ROI) based approach were used to examine the relationship between hippocampal gray matter volume (GMv) and depressive symptoms. The impact of HIV CD4 nadir and antidepressants was also investigated. Both VBM and ROI approaches revealed that higher BDI-II scores (implicating more severe depressive symptoms) were associated with loss of hippocampal GMv, especially in the right hippocampus and the right entorhinal cortex. Low CD4 nadir predicted additional hippocampal volume loss independent of depressive symptoms. Taking antidepressants did not have a detectable effect on hippocampal volume. In summary, having more depressive symptoms is associated with smaller hippocampal volume in PWH, and a history of severe immunosuppression (i.e., low CD4 nadir) correlates with additional hippocampal volume reduction. However, the impact of depression on hippocampal volume may be independent of HIV-disease severity such as low CD4 nadir.
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http://dx.doi.org/10.1002/hbm.25451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288081PMC
August 2021

Large Mitochondrial DNA Deletions in HIV Sensory Neuropathy.

Neurology 2021 07 4;97(2):e156-e165. Epub 2021 May 4.

From the Department of Neurology (R.H.R., W.C., K.P., L.H.R., J.C.M., A.H., M.P.) and Department of Psychiatry (L.H.R.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Medicine (D.B.), Brigham and Women's Hospital, Boston, MA; Departments of Neurosciences and Psychiatry (R.J.E., M.M.D.) and Department of Medicine (A.B., M.F.O.), University of California, San Diego; Department of Neurology (D.B.C.), Washington University School of Medicine, St. Louis, MO; Departments of Genomic Medicine, Medicine, and Pediatrics (A.R.K.), Cleveland Clinic/Lerner Research Institute and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, OH; and Department of Pathology and Laboratory Medicine (C.G.), Joint Appointment in Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA.

Objective: The primary objective of this study was to evaluate the correlation of large mitochondrial DNA (mtDNA) deletions in skin samples of people with HIV (PWH) with measures of neuropathy and prior exposure to therapy. We hypothesized that deletions would be associated with neuropathy. As secondary objectives, we determined the correlation of deletion burden with demographic data and neuropathy measures.

Methods: In this retrospective cohort study, we measured the accumulation of large mtDNA deletions in skin biopsies from PWH recruited as part of the AIDS Clinical Trials Group (ACTG). Our cohort includes individuals with and without sensory neuropathy, as well as individuals with normal or abnormal skin biopsies. Skin biopsies, sural and peroneal nerve conduction studies, total neuropathy score, and deletion burden scores were measured, along with baseline demographic data such as age, CD4+ cell count, viral counts, and prior nucleoside reverse transcriptase inhibitor exposures.

Results: Sixty-seven PWH were enrolled in the study. The mean age of the cohort (n = 67) was 44 years (SD 6.8, range 32-65 years), and 9 participants were female. The mean CD4+ T-cell count was 168 cells/mm (SD 97 cells/mm, range 1-416 cells/mm) and mean viral load was 51,129 copies/mL (SD 114,586 copies/mL, range 147-657,775 copies/mL). We determined that there was a correlation between the total mtDNA deletion and intraepidermal nerve fiber density (IENFD) ( = -0.344, = 0.04) and sural nerve amplitude ( = -0.359, = 0.004).

Conclusions: Both IENFD and sural nerve amplitude statistically correlate with mitochondrial mutation burden in PWH, specifically in those with HIV-associated sensory neuropathy as assessed by skin biopsy.
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http://dx.doi.org/10.1212/WNL.0000000000012142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279564PMC
July 2021

Cannabis and the Gut-Brain Axis Communication in HIV Infection.

Cannabis Cannabinoid Res 2021 04 15;6(2):92-104. Epub 2021 Apr 15.

Departments of Neurosciences and Psychiatry, University of California, San Diego, San Diego, California, USA.

People living with HIV infection (PWH) disclose that cannabis is an effective strategy for alleviating symptoms associated with HIV disease. However, some medical providers feel ill-informed to engage in evidence-based conversations. HIV leads to alterations in the gut microbiome, gut-brain axis signaling, and chronic inflammation. The endocannabinoid system regulates homeostasis of multiple organ systems. When deficient, dysregulation of the gut-brain axis can result in chronic inflammation and neuroinflammation. Cannabis along with the naturally occurring endocannabinoids has antioxidant and anti-inflammatory properties that can support healing and restoration as an adjunctive therapy. The purpose of this literature review is to report the physiologic mechanisms that occur in the pathology of HIV and discuss potential benefits of cannabinoids in supporting health and reducing the negative effects of comorbidities in PWH.
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http://dx.doi.org/10.1089/can.2020.0037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064951PMC
April 2021

Low-Level HIV RNA in Cerebrospinal Fluid and Neurocognitive Performance: A Longitudinal Cohort Study.

J Acquir Immune Defic Syndr 2021 Aug;87(5):1196-1204

Department of Psychiatry, University of California, San Diego, CA.

Background: Cognitive complications persist in persons with HIV during suppressive antiretroviral therapy (ART). Low levels of HIV during ART could contribute to these complications. In this study, we measured cerebrospinal fluid (CSF) HIV using a single-copy assay (SCA) to investigate a possible relationship between low-level HIV and cognition.

Design/methods: SCA data were analyzed from 3 consecutively paired CSF-plasma specimens collected over a mean of 456 days from 96 participants on suppressive ART. Using mixed models, the presence of CSF HIV by SCA as a risk factor for worse neurocognitive performance was examined.

Results: At baseline on the SCA, 45.8% of participants had detectable plasma HIV RNA (median 8 copies/mL and interquartile range = 3-17 among detectable values) and 17.7% had detectable CSF HIV RNA (median CSF concentration= 3 copies/mL and interquartile range= 2-13 among detectable values). The frequency of CSF HIV RNA detection declined over time in CSF (P = 0.018) with a trend toward decline in plasma (P = 0.064). Detectable CSF HIV RNA during the study was associated with worse performance in the domains of recall (P = 0.014) and motor (P = 0.040) and a trend with worse overall global performance (P = 0.078). Integrase inhibitor use, although very infrequent in this cohort, was associated with better performance in 2 domains.

Conclusions: Low-level CSF HIV RNA declines with time but is associated with worse cognitive performance in 2 domains. Additional research is needed to better understand the relationship between HIV RNA persistence during long-term ART and central nervous system complications in persons with HIV.
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http://dx.doi.org/10.1097/QAI.0000000000002714DOI Listing
August 2021

IgG intrathecal synthesis in HIV-associated neurocognitive disorder (HAND) according to the HIV-1 subtypes and pattern of HIV RNA in CNS and plasma compartments.

J Neuroimmunol 2021 06 8;355:577542. Epub 2021 Mar 8.

HIV Neurobehavioral Research Center, University of California, San Diego, San Diego, CA, USA.

We hypothesized that humoral immunity stimulation in the CNS in HIV-1C patients would be lower than that in HIV-1B due to a defective Tat chemokine dimotif (C30C31) that might influence cellular trafficking and CNS inflammation. Sixty-eight paired CSF and blood samples from people with HIV (PWH), free of CNS opportunistic infections, were included, HIV-1B (n = 27), HIV-1C (n = 26), and HIV negative (n = 25). IgG intrathecal synthesis was assayed using quantitative and qualitative methods. IgG oligoclonal bands (OCB) in CSF were observed in 51% of PWH, comparable between HIV-1B and HIV-1C, as well as the medians of IgG intrathecal synthesis formulas. The group with HIV infection aviremic in CSF and blood showed 75% of OCB. There was a poor positive correlation between the IgG quotient and GDS. The impact of HIV-1 on IgG intrathecal production was not subtype dependent. Low-grade CNS intrathecal IgG production persists in HIV CNS infection even in PWH with CSF and blood HIV RNA controlled.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102367PMC
June 2021

Detection of H3K4me3 Identifies NeuroHIV Signatures, Genomic Effects of Methamphetamine and Addiction Pathways in Postmortem HIV+ Brain Specimens that Are Not Amenable to Transcriptome Analysis.

Viruses 2021 03 24;13(4). Epub 2021 Mar 24.

San Diego Biomedical Research Institute, San Diego, CA 92121, USA.

Human postmortem specimens are extremely valuable resources for investigating translational hypotheses. Tissue repositories collect clinically assessed specimens from people with and without HIV, including age, viral load, treatments, substance use patterns and cognitive functions. One challenge is the limited number of specimens suitable for transcriptional studies, mainly due to poor RNA quality resulting from long postmortem intervals. We hypothesized that epigenomic signatures would be more stable than RNA for assessing global changes associated with outcomes of interest. We found that H3K27Ac or RNA Polymerase (Pol) were not consistently detected by Chromatin Immunoprecipitation (ChIP), while the enhancer H3K4me3 histone modification was abundant and stable up to the 72 h postmortem. We tested our ability to use HeKme in human prefrontal cortex from HIV+ individuals meeting criteria for methamphetamine use disorder or not (Meth +/-) which exhibited poor RNA quality and were not suitable for transcriptional profiling. Systems strategies that are typically used in transcriptional metadata were applied to H3K4me3 peaks revealing consistent genomic activity differences in regions where addiction and neuronal synapses pathway genes are represented, including genes of the dopaminergic system, as well as inflammatory pathways. The resulting comparisons mirrored previously observed effects of Meth on suppressing gene expression and provided insights on neurological processes affected by Meth. The results suggested that H3K4me3 detection in chromatin may reflect transcriptional patterns, thus providing opportunities for analysis of larger numbers of specimens from cases with substance use and neurological deficits. In conclusion, the detection of H3K4me3 in isolated chromatin can be an alternative to transcriptome strategies to increase the power of association using specimens with long postmortem intervals and low RNA quality.
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http://dx.doi.org/10.3390/v13040544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064323PMC
March 2021

Gut microbiota dysbiosis is associated with worse emotional states in HIV infection.

J Neurovirol 2021 04 2;27(2):228-238. Epub 2021 Mar 2.

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

The biological mechanisms underlying emotional distress in HIV infection are likely to be complex but remain understudied. We investigated whether dysbiotic signatures in the gut microbiome of persons living with HIV (PLWH) are associated with their emotional status. We retrospectively examined the gut microbiome and clinical evaluation of 129 adults (94 PLWH and 35 HIV-) enrolled at UC San Diego's HIV Neurobehavioral Research Program. A subset of participants (32 PLWH vs. 13 HIV-) underwent an emotional assessment using the NIH Toolbox Emotion Battery summarized by three composite scores (negative affect, social satisfaction, and psychological well-being). We then sequenced the 16S rDNA V3-V4 regions from stool and performed taxonomic assignment using CLC Microbial Genomics Module. The gut microbiota profiles were evaluated in relation to participants' emotional assessment. All analyses were done in R statistical software. We found that the relative abundance of aerotolerant bacteria was significantly higher in PLWH (p < 0.01) and was associated with a lifetime major depression diagnosis independently of HIV status (p = 0.05). Moreover, PLWH experienced significantly worse psychological well-being (p = 0.02), less social satisfaction (p = 0.03), and more negative affect (p = 0.02). Higher levels of aerotolerant bacteria were associated with worse psychological well-being (rho = -0.35, p = 0.02), less social satisfaction (r = - 0.42, p < 0.01), and more negative affect (rho = 0.46, p < 0.01). The association of aerotolerant bacteria with social satisfaction and negative affect was independent of HIV status (p < 0.05, for both). The over-representation of aerotolerant bacteria in the gut may reflect worse oxidative stress and barrier defects and may contribute to emotional distress during HIV infection.
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http://dx.doi.org/10.1007/s13365-020-00933-1DOI Listing
April 2021

Telomere length is associated with HIV infection, methamphetamine use, inflammation, and comorbid disease risk.

Drug Alcohol Depend 2021 04 16;221:108639. Epub 2021 Feb 16.

Department of Medicine University of California San Diego, 9500 Gilman Drive La Jolla, CA, 92093, USA.

Background: HIV infection and methamphetamine dependence (METH) are each associated with inflammation and premature aging, but their impact on biological aging is difficult to measure. Here we examined the impact of HIV and METH on leukocyte telomere lengths (LTL), and the correlations between LTL and other aging biomarkers.

Methods: The study was a cross-sectional analysis of 161 individuals categorized by HIV and methamphetamine (METH) dependence status into four groups: HIV-METH- (n = 50), HIV-METH+ (n = 29), HIV + METH- (n = 40), and HIV + METH+ (n = 42). We analyzed the relationships of leukocyte telomere length (telomere to single copy gene [T/S] ratio) with demographic and clinical data as well as a panel of biomarkers of inflammation and endothelial activation measured in blood and cerebrospinal fluid (CSF).

Results: HIV and METH were independently associated with shorter T/S ratio, even after adjusting for demographics and leukocyte count (R = 0·59, p < 0·0001). Higher plasma C-reactive protein (p = 0·0036) and CSF VCAM-1 (p = 0·0080) were also associated with shorter T/S ratio. A shorter T/S ratio was associated with higher risk for cardiovascular disease (p < 0·0001) and stroke (p < 0·0001), worse motor functioning (p = 0·037) and processing speed (p = 0·023), more depressive symptoms (p = 0·013), and higher CSF neurofilament-light (p = 0·003).

Conclusions: HIV and METH dependence were each associated with shorter telomeres. After adjusting for demographics, HIV, and METH, T/S ratio remained associated with aging-related outcomes including neurocognitive impairment, neurodegeneration, risks of cardiovascular disease and stroke. While not establishing causality, this study supports using the T/S ratio as a biomarker for estimating the impact of HIV and comorbidities on long-term health.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.108639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026664PMC
April 2021

Low CD4+ cell count nadir exacerbates the impacts of APOE ε4 on functional connectivity and memory in adults with HIV.

AIDS 2021 04;35(5):727-736

Department of Neuroscience.

Objective: Nearly half of individuals living with HIV in the USA are now 50 or older. This rapidly ageing populace may be at an increasingly greater risk of Alzheimer's disease. However, the potential interaction between HIV-disease and Alzheimer's disease pathogenesis (i.e. Alzheimer's disease genetic risk factors) on brain function remains an open question. The present study aimed to investigate the impact of APOE ε4 on brain function in middle-aged to older people with HIV (PWH), as well as the putative interaction between ε4 and HIV disease severity.

Methods: Ninety-nine PWH participated in a cross-sectional study (56.3 ± 6.5 years, range 41-70 years, 27 women, 26 ε4 carriers and 73 noncarriers). Structural MRI and resting-state functional MRI were collected to assess alterations in brain structure and functional connectivity, respectively.

Results: APOE ε4 was associated with worse memory performance and reduced functional connectivity in the memory network. The functional connectivity reduction was centred at the caudate nucleus rather than hippocampus and correlated with worse memory performance. In ε4 carriers, low CD4+ cell count nadir was associated with reduced functional connectivity in the memory network, but this association was absent in noncarriers. Furthermore, there was an indirect detrimental impact of ε4 on memory performance through memory network functional connectivity. However, this indirect effect was contingent on CD4+ cell count nadir, that is the indirect effect of ε4 on memory was only significant when CD4+ cell count nadir was low.

Interpretation: APOE ε4 is associated with reduced memory and reduced functional connectivity within the memory network, and low CD4+ cell count nadir -- indicating a history of severe immunosuppression -- may exacerbate the effects of ε4.
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http://dx.doi.org/10.1097/QAD.0000000000002840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318747PMC
April 2021

Cerebrospinal fluid CXCL10 is associated with the presence of low level CSF HIV during suppressive antiretroviral therapy.

J Neuroimmunol 2021 04 21;353:577493. Epub 2021 Jan 21.

Department of Psychiatry, University of California at San Diego School of Medicine, 220 Dickinson Street, San Diego, CA 92103-8231, United States of America; Department of Medicine, University of California at San Diego School of Medicine, 220 Dickinson Street, San Diego, CA 92103-8231, United States of America.

Surrogate markers of HIV central nervous system (CNS) persistence are needed because direct HIV measurements from the CNS require specialized protocols and are not always detectable or quantifiable. We analyzed paired plasma and CSF samples from people with HIV (PWH) on suppressive therapy (ART) with a validated HIV single copy RNA assay. Two potential markers of CNS persistence were measured (CXCL10 and sCD30). We then examined associations with CSF HIV RNA positivity in univariable and multivariable analyses. Among 66 individuals, 18.2% had detectable CSF HIV. Individuals who had detectable HIV in CSF had higher CSF CXCL10 concentrations (median 514 pg/ml versus median 317 pg/ml, p = 0.019), but did not have significantly different CSF sCD30 concentrations (median 7.5 ng/ml versus median 7.6 ng/ml, p = 0.78). In the multiple logistic analysis, both higher CSF CXCL10 (p = 0.038) and plasma HIV detectability (p = 0.035) were significantly associated with detectable CSF HIV. Both sCD30 and CXCL10 correlated positively with NfL and NSE, two neuronal markers. This study demonstrates that CSF CXCL10 concentrations reflect low level HIV CNS persistence despite virologic suppression on ART. Given that it is readily detectable and quantifiable, this chemokine may be a promising biomarker to evaluate HIV eradication therapies that target the CNS.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577493DOI Listing
April 2021

Paresthesia Predicts Increased Risk of Distal Neuropathic Pain in Older People with HIV-Associated Sensory Polyneuropathy.

Pain Med 2021 08;22(8):1850-1856

Department of Neurosciences, University of California, San Diego, La Jolla, California.

Objective: Distal sensory polyneuropathy (DSP) is a disabling consequence of human immunodeficiency virus (HIV), leading to poor quality of life and more frequent falls in older age. Neuropathic pain and paresthesia are prevalent symptoms; however, there are currently no known curative treatments and the longitudinal course of pain in HIV-associated DSP is poorly characterized.

Methods: This was a prospective longitudinal study of 265 people with HIV (PWH) enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study with baseline and 12-year follow-up evaluations. Since pain and paresthesia are highly correlated, statistical decomposition was used to separate the two symptoms at baseline. Multivariable logistic regression analyses of decomposed variables were used to determine the effects of neuropathy symptoms at baseline on presence and worsening of distal neuropathic pain at 12-year follow-up, adjusted for covariates.

Results: Mean age was 56 ± 8 years, and 21% were female at follow-up. Nearly the entire cohort (96%) was on antiretroviral therapy (ART), and 82% had suppressed (≤50 copies/mL) plasma viral loads at follow-up. Of those with pain at follow-up (n = 100), 23% had paresthesia at the initial visit. Decomposed paresthesia at baseline increased the risk of pain at follow-up (odds ratio [OR] 1.56; 95% confidence interval [CI] 1.18, 2.07), and decomposed pain at baseline predicted a higher frequency of pain at follow-up (OR 1.96 [95% CI 1.51, 2.58]).

Conclusions: Paresthesias are a clinically significant predictor of incident pain at follow-up among aging PWH with DSP. Development of new therapies to encourage neuroregeneration might take advantage of this finding to choose individuals likely to benefit from treatment preventing incident pain.
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http://dx.doi.org/10.1093/pm/pnab056DOI Listing
August 2021

Plasma Citrate and Succinate Are Associated With Neurocognitive Impairment in Older People With HIV.

Clin Infect Dis 2021 08;73(3):e765-e772

Center for Mitochondrial Disease and Department of Pharmacology, Case Western Reserve University and Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Background: Neurocognitive impairment (NCI) is associated with monocyte activation in people with HIV (PWH). Activated monocytes increase glycolysis, reduce oxidative phosphorylation, and accumulate citrate and succinate, tricarboxylic acid (TCA) cycle metabolites that promote inflammation-this metabolic shift may contribute to NCI and slowed gait speed in PWH.

Methods: Plasma citrate and succinate were assayed by liquid chromatography-mass spectrometry from 957 participants upon entry to a multicenter, prospective cohort of older PWH. Logistic, linear, and mixed-effects linear regression models were used to examine associations between entry/baseline TCA cycle metabolites and cross-sectional and longitudinal NCI, neuropsychological test scores (NPZ-4), and gait speed.

Results: Median age was 51 (range 40-78) years. Each 1 standard deviation (SD) citrate increment was associated with 1.18 higher odds of prevalent NCI at baseline (P = .03), 0.07 SD lower time-updated NPZ-4 score (P = .01), and 0.02 m/s slower time-updated gait speed (P < .0001). Age accentuated these effects. In the oldest age-quartile, higher citrate was associated with 1.64 higher odds of prevalent NCI, 0.17 SD lower NPZ-4, and 0.04 m/s slower gait speed (P ≤ .01 for each). Similar associations were apparent with succinate in the oldest age-quintile, but not with gait speed. In participants without NCI at entry, higher citrate predicted a faster rate of neurocognitive decline.

Conclusions: Higher plasma citrate and succinate are associated with worse cross-sectional and longitudinal measures of neurocognitive function and gait speed that are age-dependent, supporting the importance of altered bioenergetic metabolism in the pathogenesis of NCI in older PWH.
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http://dx.doi.org/10.1093/cid/ciab107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326582PMC
August 2021

Cannabis use is not associated with increased balance disturbances in HIV-infected individuals.

J Cannabis Res 2021 Feb 3;3(1). Epub 2021 Feb 3.

University of California San Diego, San Diego, USA.

Background: The association between long-term cannabis use and balance disturbances has not been investigated in people living with HIV (PWH). We hypothesized that long-term cannabis use in PWH might be associated with more deleterious effects on balance than in HIV seronegative individuals due to potential neurotoxic interactions between HIV and cannabis.

Methods: Three thousand six-hundred and forty-eight participants with and without HIV completed an interviewer-administered timeline follow-back assessment to assess lifetime days and quantity of cannabis use and other cannabis use characteristics. A structured clinical interview was used to collect any history of balance disturbance. Comparisons between HIV+ vs the HIV- groups and moderate-severe vs. no or minimal imbalance in participant characteristics (demographics, cannabis use, medication currently used, and neurological disease) were performed using Student t tests for continuous variables and Fisher's exact test for binary and categorical variables. Multivariate logistic regression was applied to determine the interaction effect of total quantity of cannabis use with HIV status on balance disturbance. Age, gender, cDSPN symptoms, gait ataxia, opioid medications, and sedatives were included as covariates in the adjusted model after variable selection. The effect sizes are presented as Cohen's d or odds ratios.

Results: On average, participants were 45.4 years old (SD = 11 years), primarily male (77.7%), and non-Hispanic white (48.1%). A majority of participants were HIV+ (79.1%). Four hundred thirty (11.9%) of the participants reported balance disturbances within the past 10 years. PWH were more likely to have balance disturbances than demographically matched HIV-uninfected participants (odds ratio [OR] 2.66, 95% CI 1.91-3.7). Participants with moderate-severe balance disturbances did not differ from those with no or minimal imbalance in the proportion who had ever used cannabis (73.8% vs. 74.4%; p = 0.8) (OR 1.03, 95% CI 0.80-1.32) neither did they have a higher total amount of cannabis use (4871 vs. 4648; p = 0.3) (Cohen's d 0.11, 95% CI 0.01-0.14). In the HIV- population, those with balance disturbances reported more total amount of cannabis use as compared to those with normal balance (11316 vs 4154; p = 0.007). In the HIV+ population on the other hand, there was no significant association (4379 vs 4773; p = 0.6).

Conclusions: We found unexpectedly that while long-term cannabis use in HIV- individuals was associated with more severe balance disturbances, there were no associations in HIV+ individuals. This suggests that cannabis use in HIV is safe with respect to balance disturbances. Given that HIV is related to persistent inflammation despite virologic suppression on antiretroviral therapy, future mechanistic studies are needed to determine whether HIV-associated inflammation contributes to the higher prevalence of balance disturbance in HIV+ individuals and whether cannabinoids have anti-inflammatory effects that mitigate HIV-associated balance disturbance.
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http://dx.doi.org/10.1186/s42238-021-00059-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860021PMC
February 2021

HIV-1C and HIV-1B Tat protein polymorphism in Southern Brazil.

J Neurovirol 2021 02 18;27(1):126-136. Epub 2021 Jan 18.

University of California-San Diego, San Diego, CA, USA.

The transactivator of transcription (Tat) is a key HIV regulatory protein. We aimed to identify the frequency of key polymorphisms in HIV-1C compared with HIV-1B Tat protein, chiefly in the cysteine-, arginine-, and glutamine-rich domains and identify novel point mutations in HIV-1B and C sequences from Southern Brazil. This study was the first to investigate the genetic diversity and point mutations within HIV-1 Tat C in a Brazilian cohort. This was an observational, cross-sectional study, which included sequences of HIV-1B (n = 20) and HIV-1C (n = 21) from Southern Brazil. Additionally, 344 HIV-1C sequences were obtained from the Los Alamos database: 29 from Brazil and 315 from Africa, Asia, and Europe. The frequency of C31S substitution on HIV-1 Tat C in Brazil was 82% vs. 10% in the HIV-1B group (p < 0.0001). The frequency of the R57S substitution among the HIV-1C sequences from Brazil was 74% vs. 20% in HIV-1B (p = 0.004), and that of substitution Q63E in HIV-1C was 80% and 20% in HIV-1B (p < 0.0001). The mutation P60Q was more frequent in HIV-1B than in HIV-1C (55% and 6.12%, respectively, p < 0.0001)). Novel point mutations in the HIV-1C and B Tat functional domains were described. The frequency of C31S and other key point mutations in HIV-1 Tat C in Brazil were similar to those described in Africa, although lower than those in India. The Tat-B and C sequences found in Southern Brazil are consistent with biological differences and have potential implications for HIV-1 subtype pathogenesis.
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http://dx.doi.org/10.1007/s13365-020-00935-zDOI Listing
February 2021

Chronically elevated depressive symptoms interact with acute increases in inflammation to predict worse neurocognition among people with HIV.

J Neurovirol 2021 02 6;27(1):160-167. Epub 2021 Jan 6.

Department of Psychiatry, University of California, La Jolla, San Diego, CA, USA.

We examined the joint effects of depressive symptoms (Beck Depression Inventory-II (BDI-II)) and systemic inflammation (plasma C-reactive protein (CRP)) on longitudinal profiles of neurocognition in a cohort of 143 people with HIV (PWH) on antiretroviral therapy. Global neurocognition, processing speed, motor skills, and attention/working memory all worsened as CRP increased but only among PWH who, on average, exhibited moderate to severe depressive symptoms (BDI-II > 22). Findings suggest that some PWH with chronically elevated depressive symptoms may have an inflammatory subtype of depression and a particular vulnerability to neurocognitive changes that may respond to drugs targeting inflammation or its neural sequelae.
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http://dx.doi.org/10.1007/s13365-020-00925-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284079PMC
February 2021

Social Isolation Is Linked to Inflammation in Aging People With HIV and Uninfected Individuals.

J Acquir Immune Defic Syndr 2021 04;86(5):600-606

Psychiatry; and.

Background: Even in the era of suppressive antiretroviral therapy, people with HIV (PWH) suffer greater exposure to inflammation than their uninfected peers. Although poor social support and social isolation have been linked to systemic inflammation in the general population, it is not known whether this is true also among PWH.

Methods: People with and without HIV infection were enrolled in a community-based, single-center study. Primary predictors were the Medical Outcomes Study Social Support Survey, and outcomes were a panel of inflammatory biomarkers (ICAM-1, MCP-1, IL-6, IL-8, IP-10, C-reactive protein, D-dimer, VEGF, sCD14, and uPAR) in blood plasma and cerebrospinal fluid (CSF).

Results: PWH had worse positive social support (P = 0.0138) and affectionate support (P = 0.0078) than did HIV- individuals. A factor analysis was used to group the biomarkers into related categories separately for each fluid. Levels of 3 of the 4 plasma factors were significantly higher in PWH than HIV- (ps = 0.007, 0.001, and 0.0005, respectively). Levels of 1 of the 3 CSF factors also were significantly higher in PWH than HIV- (P = 0.0194). In the combined PWH and HIV- cohort, poorer social support was associated with higher levels of a factor in plasma loading on MCP-1, IL-8, and VEGF (P = 0.020) and with a CSF factor loading on MCP-1 and IL-6 (P = 0.006).

Conclusion: These results suggest that enhancing social support might be an intervention to reduce inflammation and its associated adverse outcomes among PWH.
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http://dx.doi.org/10.1097/QAI.0000000000002596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933098PMC
April 2021

Nucleic acid oxidation is associated with biomarkers of neurodegeneration in CSF in people with HIV.

Neurol Neuroimmunol Neuroinflamm 2020 11 14;7(6). Epub 2020 Oct 14.

From the Departments of Neurosciences and Psychiatry, University of California (R.J.E.), San Diego; Department of Psychiatry, University of California (D.J.M., E.E.S., R.K.H.), San Diego; Department of Medicine, University of California (S.M., T.H.), San Diego; Vanderbilt University (D.S., J.A.F.), Nashville, Tennessee; and Departments of Medicine and Psychiatry, University of California (S.L.L.), San Diego.

Objective: To determine whether oxidative stress in virologically suppressed people with HIV (PWH) may contribute to or result from neurodegeneration, we measured 7,8-dihydro-8-oxoguanine (8-oxo-dG), a marker of DNA damage due to oxidative stress, and markers of age-related neurodegeneration, specifically, reduced levels of CSF Aβ-42, and elevated CSF total tau and neurofilament light (NFL).

Methods: This cross-sectional study prospectively enrolled participants at 6 US centers in the CNS HIV Antiretroviral Effects Research study. Inclusion criteria included HIV+ with a plasma level of HIV RNA ≤50 copies/mL. Exclusions included significant CNS confounding conditions. Measurements of total tau and Aβ-42 were performed by bead suspension array. NFL and 8-oxo-dG were measured using ELISA.

Results: Participants were 53 PWH, mean age 55 (±9.3) years, 19% women, and 48% non-Hispanic White. Higher 8-oxo-dG correlated with markers of AD-related neurodegeneration including lower CSF Aβ-42 (r = -0.34; = 0.012) and higher CSF NFL (r = 0.39; = 0.0091) and total tau (r = 0.6696; < 0.0001). Relationships remained after adjusting for demographic variables. Levels of protein carbonyls, a marker of protein oxidation, were not related to neurodegeneration markers.

Conclusions: Among virologically suppressed PWH, nucleic acid oxidation was associated with standard CSF biomarkers of neurodegeneration. Potential sources of oxidative stress in PWH include low-level HIV replication, inflammation, mitochondrial dysfunction, and specific antiretroviral drugs. Results suggest that the higher levels of oxidative stress among PWH may play a role in neurodegeneration.

Classification Of Evidence: This study provides Class II evidence that among virologically suppressed PWH, nucleic acid oxidation is associated with standard CSF biomarkers of neurodegeneration.
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http://dx.doi.org/10.1212/NXI.0000000000000902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577534PMC
November 2020

Reduced Independence in Daily Living Is Associated with the Gut Microbiome in People with HIV and HCV.

mSystems 2020 Oct 13;5(5). Epub 2020 Oct 13.

Center for Microbiome Innovation, University of California San Diego, La Jolla, California, USA

Alterations in the gut microbiome are associated with neurocognition and related disorders, including in the context of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection. However, the connection between the gut microbiome and cognitive decline, gauged by increased dependence in instrumental activities of daily living (IADL), remains largely unexplored in the context of these diseases. Here we characterized the gut microbiome using 16S rRNA amplicon sequencing and untargeted metabolomics with liquid chromatography-mass spectrometry from 347 people with HIV, HIV and HCV, or neither, all of whom underwent a comprehensive neuropsychiatric assessment. We observed that IADL-dependent and -independent HIV-monoinfected (HIV-positive [HIV+]/HCV-negative [HCV-]) and coinfected (HIV+/HCV+) individuals have distinct gut microbiomes. Moreover, we found that dependent individuals with HIV or HIV and HCV were enriched in These results may have implications for the characterization of cognitive decline, as well as the development of potential prevention and treatment strategies for individuals infected with HIV and/or HCV. Of particular interest is the possibility that dietary interventions that are known to modify the microbiome could be used to shift the microbiome toward more favorable states for preserving independence. The microbes in the gut and the chemicals they produce by metabolism have been linked to brain function. In earlier work, we showed that infection with two viruses, HIV and HCV, changed the gut microbes and metabolism in ways that were associated with a lifetime history of major depressive disorder. Here, we extend this analysis looking at a measurement of independence in daily living. We find that in individuals with HIV, whether or not they also have HCV, those who reported reduced independence were enriched in a genus of bacteria called This result is interesting because is strongly associated with diets low in carbohydrates and high in animal protein, suggesting that diet changes may help preserve independent living in people living long-term with HIV (although clinical intervention trials would be needed in order to confirm this).
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http://dx.doi.org/10.1128/mSystems.00528-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567581PMC
October 2020

Depression in Individuals Coinfected with HIV and HCV Is Associated with Systematic Differences in the Gut Microbiome and Metabolome.

mSystems 2020 Sep 29;5(5). Epub 2020 Sep 29.

Center for Microbiome Innovation, University of California San Diego, La Jolla, California, USA

Depression is influenced by the structure, diversity, and composition of the gut microbiome. Although depression has been described previously in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) monoinfections, and to a lesser extent in HIV-HCV coinfection, research on the interplay between depression and the gut microbiome in these disease states is limited. Here, we characterized the gut microbiome using 16S rRNA amplicon sequencing of fecal samples from 373 participants who underwent a comprehensive neuropsychiatric assessment and the gut metabolome on a subset of these participants using untargeted metabolomics with liquid chromatography-mass spectrometry. We observed that the gut microbiome and metabolome were distinct between HIV-positive and -negative individuals. HCV infection had a large association with the microbiome that was not confounded by drug use. Therefore, we classified the participants by HIV and HCV infection status (HIV-monoinfected, HIV-HCV coinfected, or uninfected). The three groups significantly differed in their gut microbiome (unweighted UniFrac distances) and metabolome (Bray-Curtis distances). Coinfected individuals also had lower alpha diversity. Within each of the three groups, we evaluated lifetime major depressive disorder (MDD) and current Beck Depression Inventory-II. We found that the gut microbiome differed between depression states only in coinfected individuals. Coinfected individuals with a lifetime history of MDD were enriched in primary and secondary bile acids, as well as taxa previously identified in people with MDD. Collectively, we observe persistent signatures associated with depression only in coinfected individuals, suggesting that HCV itself, or interactions between HCV and HIV, may drive HIV-related neuropsychiatric differences. The human gut microbiome influences depression. Differences between the microbiomes of HIV-infected and uninfected individuals have been described, but it is not known whether these are due to HIV itself, or to common HIV comorbidities such as HCV coinfection. Limited research has explored the influence of the microbiome on depression within these groups. Here, we characterized the microbial community and metabolome in the stools from 373 people, noting the presence of current or lifetime depression as well as their HIV and HCV infection status. Our findings provide additional evidence that individuals with HIV have different microbiomes which are further altered by HCV coinfection. In individuals coinfected with both HIV and HCV, we identified microbes and molecules that were associated with depression. These results suggest that the interplay of HIV and HCV and the gut microbiome may contribute to the HIV-associated neuropsychiatric problems.
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http://dx.doi.org/10.1128/mSystems.00465-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527136PMC
September 2020
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