The Influence of HLA on HIV-Associated Neurocognitive Impairment in Anhui, China

HLA-DR*04 was identified as a predictor of HIV-Associated neurocognitive disorder (HAND), low CD4 T-cell responses to HIV, and low plasma HIV RNA levels in a U.S. cohort. We hypothesized that low CD4 T-cell activation leads to poor immune control of HIV in the CNS, predisposing to HAND, but also provided fewer target (activated CD4 T-cells) for HIV replication. To assess the consistency of these HLA Class II associations in a new cohort and extend analysis to HLA Class I, HLA types, neurocognitive, and virologic status were examined in a cohort of former plasma donors in China.178 HIV infected individuals in Anhui China, were HLA typed and underwent neurocognitive evaluations (using locally standardized norms), neuromedical, treatment and virologic assessments at baseline and at 12 months.HLA DR*04 was associated with a higher rate of baseline neurocognitive impairment (p = 0.04), neurocognitive decline (p = 0.04), and lower levels of HIV RNA in plasma (p = 0.05). HLA Class I alleles (B*27,57,58,A*03,33) that specify a CD8 T-cell response to conserved HIV sequences were neuroprotective, associated with less impairment at baseline (p = 0.037), at month 012 (p = 0.013) and less neurocognitive decline (p = 0.023) in the interval. Consistent with the theory that effective CD8 T-cell responses require CD4 T-cell support, the HLA DR*04 allele reduced the neuroprotective effect of the Class I alleles. The presence of HLA-DR*04 and the Alzheimer associated allele ApoE4 in the same individual had a synergistic negative effect on cognition (p = 0.003).Despite major background differences between U.S. and Anhui China cohorts, HLA DR*04 predicted neurocognitive impairment and lower plasma HIV RNA levels in both populations. HLA Class I alleles associated with CD8 T-cell control of HIV were associated with protection from HAND, but protection was reduced in the presence of HLA-DR*04

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Beyond the Syndemic of Opioid Use Disorders and HIV: The Impact of Opioids on Viral Reservoirs

People with HIV are more likely to have opioid use disorder and to be prescribed opioids for chronic pain than the general population; however, the effects of opioids on the immune system and HIV persistence have not been fully elucidated. Opioids may affect HIV reservoirs during their establishment, maintenance, and reactivation by enhancing HIV infectivity and replication due to upregulation of co-receptors and impairment of innate antiviral responses. Opioids may also modulate immune cell functioning and microbial translocation and can reverse viral latency. In this review, we summarize the current findings for and against the modulating effects of opioids on HIV cellular and anatomical reservoirs, highlighting the current limitations that affect in vitro, ex vivo, and in vivo studies in the field. We propose further research targets and potential strategies to approach this topic

Lessons for Understanding Central Nervous System HIV Reservoirs from the Last Gift Program

Purpose of reviewDeep tissue HIV reservoirs, especially within the central nervous system (CNS), are understudied due to the challenges of sampling brain, spinal cord, and other tissues. Understanding the cellular characteristics and viral dynamics in CNS reservoirs is critical so that HIV cure trials can address them and monitor the direct and indirect effects of interventions. The Last Gift program was developed to address these needs by enrolling altruistic people with HIV (PWH) at the end of life who agree to rapid research autopsy.Recent findingsRecent findings from the Last Gift emphasize significant heterogeneity across CNS reservoirs, CNS compartmentalization including differential sensitivity to broadly neutralizing antibodies, and bidirectional migration of HIV across the blood-brain barrier. Our findings add support for the potential of CNS reservoirs to be a source of rebounding viruses and reseeding of systemic sites if they are not targeted by cure strategies. This review highlights important scientific, practical, and ethical lessons learned from the Last Gift program in the context of recent advances in understanding the CNS reservoirs and key knowledge gaps in current research

Approaches to identifying appropriate medication adherence assessments for HIV infected individuals with comorbid bipolar disorder.

Assessing medication adherence in already difficult-to-treat HIV-infected subpopulations presents a unique challenge. The objective of this study was to compare different approaches to assessing medication adherence: (1) electronic medication monitoring, (2) standardized self-report questionnaire, and (3) self-report visual analogue scale, and to determine whether antiretroviral therapy (ART) adherence measures differed for HIV-infected persons with bipolar disorder (HIV+ /BD+) as compared to HIV-infected persons without bipolar disorder (HIV+ /BD-). ART adherence was assessed for 74 HIV-positive participants using the Medication Event Monitoring System (MEMS), AIDS Clinical Trials Group (ACTG) adherence questionnaire, and visual analogue scale (VAS). Participants were classified as adherent or nonadherent on each measure by previously validated cutscores. Correlations and logistic regressions were used to examine associations between adherence measures and demographic and clinical variables. In the HIV+ /BD- group, significant correlations existed between each self-report measure and the MEMS. Males comprised 81% of the study population. Participants averaged 44 years of age and 13 years of education. No significant correlations were found among adherence measures in the HIV+ /BD+ group. Among participants reporting adherence on either self-report measure but classified as nonadherent based on MEMS, 94% had a diagnosis of bipolar disorder. Bipolar disorder was a significant predictor of adherence classification discordance among self-report measures. Our findings suggest that it remains difficult to assess ART adherence among HIV-positive individuals with bipolar disorder. Combined approaches of self-report and objective measures may be the best way to estimate adherence, and may provide the best basis for interventions designed to improve adherence in difficult-to-treat populations

Approaches to identifying appropriate medication adherence assessments for HIV infected individuals with comorbid bipolar disorder.

Assessing medication adherence in already difficult-to-treat HIV-infected subpopulations presents a unique challenge. The objective of this study was to compare different approaches to assessing medication adherence: (1) electronic medication monitoring, (2) standardized self-report questionnaire, and (3) self-report visual analogue scale, and to determine whether antiretroviral therapy (ART) adherence measures differed for HIV-infected persons with bipolar disorder (HIV+ /BD+) as compared to HIV-infected persons without bipolar disorder (HIV+ /BD-). ART adherence was assessed for 74 HIV-positive participants using the Medication Event Monitoring System (MEMS), AIDS Clinical Trials Group (ACTG) adherence questionnaire, and visual analogue scale (VAS). Participants were classified as adherent or nonadherent on each measure by previously validated cutscores. Correlations and logistic regressions were used to examine associations between adherence measures and demographic and clinical variables. In the HIV+ /BD- group, significant correlations existed between each self-report measure and the MEMS. Males comprised 81% of the study population. Participants averaged 44 years of age and 13 years of education. No significant correlations were found among adherence measures in the HIV+ /BD+ group. Among participants reporting adherence on either self-report measure but classified as nonadherent based on MEMS, 94% had a diagnosis of bipolar disorder. Bipolar disorder was a significant predictor of adherence classification discordance among self-report measures. Our findings suggest that it remains difficult to assess ART adherence among HIV-positive individuals with bipolar disorder. Combined approaches of self-report and objective measures may be the best way to estimate adherence, and may provide the best basis for interventions designed to improve adherence in difficult-to-treat populations

Elevated Plasma Protein Carbonyl Concentration Is Associated with More Abnormal White Matter in People with HIV

Structural brain abnormalities, including those in white matter (WM), remain common in people with HIV (PWH). Their pathogenesis is uncertain and may reflect multiple etiologies. Oxidative stress is associated with inflammation, HIV, and its comorbidities. The post-translational carbonylation of proteins results from oxidative stress, and circulating protein carbonyls may reflect this. In this cross-sectional analysis, we evaluated the associations between protein carbonyls and a panel of soluble biomarkers of neuronal injury and inflammation in plasma (N = 45) and cerebrospinal fluid (CSF, n = 32) with structural brain MRI. The volume of abnormal WM was normalized for the total WM volume (nAWM). In this multisite project, all regression models were adjusted for the scanner. The candidate covariates included demographics, HIV disease characteristics, and comorbidities. Participants were PWH on virally suppressive antiretroviral therapy (ART) and were mostly white (64.4%) men (88.9%), with a mean age of 56.8 years. In unadjusted analyses, more nAWM was associated with higher plasma protein carbonyls (p = 0.002) and higher CCL2 (p = 0.045). In the adjusted regression models for nAWM, the association with plasma protein carbonyls remained significant (FDR p = 0.018). Protein carbonyls in plasma may be a valuable biomarker of oxidative stress and its associated adverse health effects, including within the central nervous system. If confirmed, these findings would support the hypothesis that reducing oxidative stress could treat or prevent WM injury in PWH