The Long Noncoding RNA HEAL Regulates HIV-1 Replication through Epigenetic Regulation of the HIV-1 Promoter.

A major challenge in finding a cure for HIV-1/AIDS is the difficulty in identifying and eradicating persistent reservoirs of replication-competent provirus. Long noncoding RNAs (lncRNAs, >200 nucleotides) are increasingly recognized to play important roles in pathophysiology. Here, we report the first genome-wide expression analysis of lncRNAs in HIV-1-infected primary monocyte-derived macrophages (MDMs). We identified an lncRNA, which we named HIV-1-enhanced lncRNA (HEAL), that is upregulated by HIV-1 infection of MDMs, microglia, and T lymphocytes. Peripheral blood mononuclear cells of HIV-1-infected individuals show elevated levels of HEAL Importantly, HEAL is a broad enhancer of multiple HIV-1 strains because depletion of HEAL inhibited X4, R5, and dual-tropic HIV replications and the inhibition was rescued by HEAL overexpression. HEAL forms a complex with the RNA-binding protein FUS, which facilitates HIV replication through at least two mechanisms: (i) HEAL-FUS complex binds the HIV promoter and enhances recruitment of the histone acetyltransferase p300, which positively regulates HIV transcription by increasing histone H3K27 acetylation and P-TEFb enrichment on the HIV promoter, and (ii) HEAL-FUS complex is enriched at the promoter of the cyclin-dependent kinase 2 gene, CDK2, to enhance CDK2 expression. Notably, HEAL knockdown and knockout mediated by RNA interference (RNAi) and CRISPR-Cas9, respectively, prevent HIV-1 recrudescence in T cells and microglia upon cessation of azidothymidine treatment in vitro Our results suggest that silencing of HEAL or perturbation of the HEAL-FUS ribonucleoprotein complex could provide a new epigenetic silencing strategy to eradicate viral reservoirs and effect a cure for HIV-1/AIDS.IMPORTANCE Despite our increased understanding of the functions of lncRNAs, their potential to develop HIV/AIDS cure strategies remains unexplored. A genome-wide analysis of lncRNAs in HIV-1-infected primary monocyte-derived macrophages (MDMs) was performed, and 1,145 differentially expressed lncRNAs were identified. An lncRNA named HIV-1-enhanced lncRNA (HEAL) is upregulated by HIV-1 infection and promotes HIV replication in T cells and macrophages. HEAL forms a complex with the RNA-binding protein FUS to enhance transcriptional coactivator p300 recruitment to the HIV promoter. Furthermore, HEAL knockdown and knockout prevent HIV-1 recrudescence in T cells and microglia upon cessation of azidothymidine treatment, suggesting HEAL as a potential therapeutic target to cure HIV-1/AIDS

Randomized Trial of a Health Coaching Intervention to Enhance Retention in Care: California Collaborative Treatment Group 594.

Poor linkage, engagement and retention remain significant barriers in achieving HIV treatment goals in the US. HIV-infected persons entering or re-entering care across three Southern California academic HIV clinics, were randomized (1:1) to an Active, Linkage, Engagement, Retention and Treatment (ALERT) specialist for outreach and health coaching, or standard of care (SOC). The primary outcome of time to loss to follow up (LTFU) was compared using Cox proportional hazards regression modeling. No differences in the median time to LTFU (81.7 for ALERT versus 93.6 weeks for SOC; HR 1.27; p = 0.40), or time to ART initiation was observed (N = 116). Although, ALERT participants demonstrated worsening depressive symptomatology from baseline to week 48 compared to SOC (p = 0.02). The ALERT intervention did not improve engagement and retention in HIV care over SOC. Further studies are needed to determine how best to apply resources to improve retention and engagement

Short Communication: Resolution of Tenofovir Disoproxil Fumarate Induced Fanconi Syndrome with Switch to Tenofovir Alafenamide Fumarate in a HIV-1 and Hepatitis B Coinfected Patient

Fanconi syndrome is a rare adverse effect of tenofovir disoproxil fumarate (TDF). Tenofovir alafenamide fumarate (TAF) is a novel prodrug with less nephrotoxicity. We report resolution of Fanconi syndrome in a HIV and hepatitis B coinfected patient switched from TDF to TAF

“Undetectable, Now What?” HIV Provider Opinions on Barriers to Healthy Aging for Older People Living with HIV in North America

Background: People living with HIV (PLWH) experience age-associated health conditions earlier than their HIV-uninfected peers and have higher rates of co-occurring conditions that impact aging. Thus, HIV providers frequently confront issues related to HIV and aging. Objective: The objective of this project was to understand provider opinions about the care of older PLWH better. Design: This was accomplished using a quantitative survey. Participants: This study involved 681 physicians treating PLWH in North America. MAIN MEASURES: We collaborated with the Emerging Infections Network (EIN) to administer a ninequestion survey covering practice characteristics, attitudes, and perceived barriers in caring for older PLWH. Key Results: Two hundred and ninety-four (43.2%) responses were collected. Providers estimate that 35% (IQR: 25-50) of their HIV-infected patients were >50 years. The majority (72%) agreed it is difficult to care for older PLWH but had confidence in their ability to do so (85%). Most list a lack of time (55.4%) and insufficient multidisciplinary support (58.5%) as limitations to the effective management of older PLWH. Multi-morbidity was overwhelmingly perceived as the most important barrier to healthy aging (62.2%) followed by tobacco/alcohol use (10%), low income/savings (8.2%), polypharmacy (4.8%) and mental illness (4.4%). Loneliness, frailty, and cognitive difficulties were judged to be less important. In conclusion, HIV providers recognized the complexity of caring for older PLWH, and yet were confident they could care for this population. Conclusion: Multi-morbidity was identified as a major barrier to healthy aging, while syndromes such as frailty and cognitive difficulties were deemed less important despite a growing body of evidence that these geriatric syndromes are common in older PLWH

“Undetectable, Now What?” HIV Provider Opinions on Barriers to Healthy Aging for Older People Living with HIV in North America

Background: People living with HIV (PLWH) experience age-associated health conditions earlier than their HIV-uninfected peers and have higher rates of co-occurring conditions that impact aging. Thus, HIV providers frequently confront issues related to HIV and aging. Objective: The objective of this project was to understand provider opinions about the care of older PLWH better. Design: This was accomplished using a quantitative survey. Participants: This study involved 681 physicians treating PLWH in North America. MAIN MEASURES: We collaborated with the Emerging Infections Network (EIN) to administer a ninequestion survey covering practice characteristics, attitudes, and perceived barriers in caring for older PLWH. Key Results: Two hundred and ninety-four (43.2%) responses were collected. Providers estimate that 35% (IQR: 25-50) of their HIV-infected patients were >50 years. The majority (72%) agreed it is difficult to care for older PLWH but had confidence in their ability to do so (85%). Most list a lack of time (55.4%) and insufficient multidisciplinary support (58.5%) as limitations to the effective management of older PLWH. Multi-morbidity was overwhelmingly perceived as the most important barrier to healthy aging (62.2%) followed by tobacco/alcohol use (10%), low income/savings (8.2%), polypharmacy (4.8%) and mental illness (4.4%). Loneliness, frailty, and cognitive difficulties were judged to be less important. In conclusion, HIV providers recognized the complexity of caring for older PLWH, and yet were confident they could care for this population. Conclusion: Multi-morbidity was identified as a major barrier to healthy aging, while syndromes such as frailty and cognitive difficulties were deemed less important despite a growing body of evidence that these geriatric syndromes are common in older PLWH

The Impact of Number of Medications on Falls in Aging Persons with Human Immunodeficiency Virus

We aimed to evaluate the impact of polypharmacy on the risk of having a fall in older persons with HIV (PWH). PWH at least 50 years of age who were seen at our institution from September 2012 to August 2017 were included. Unique participants were selected for either a case or control cohort depending on the presence of a documented fall during the study time period. Demographics, HIV-related measures, VACS score, number of medications, as well as the impact of taking benzodiazepines and opioids were compared between the two cohorts. Fall was documented for 637 patients compared to 1534 without a fall during the same time period. Multivariable logistic regression revealed that the total number of medications, having a higher VACS score, taking an opioid, being female sex assigned at birth, and having a lower nadir CD4 count were significantly associated with higher odds of having a fall. In this cohort of older PWH, taking a higher number of non-ARV medications significantly increased the odds of having a fall. In addition, taking an opioid resulted in the highest odds of having a fall. These results suggest the importance of deprescribing and addressing opioid use in reducing the risk of having a fall in older PWH

Impact of switching to tenofovir alafenamide on weight gain as compared to maintaining a non-tenofovir alafenamide containing regimen

AbstractEvaluate the impact of switching to an anti-retroviral regimen containing tenofovir alafenamide (TAF) on weight and the development of metabolic complications compared to remaining on a non-TAF containing regimen.Single-center retrospective case-control study.We evaluated people living with human immunodeficiency virus (PLWH) who were on an anti-retroviral regimen not containing TAF and were switched to a regimen containing TAF between January 1, 2016 and September 30, 2018. The control group included PLWH on a TAF free regimen throughout the study period. The primary outcome was change in weight from baseline to 12 months postswitch. Secondary outcomes included percent change in weight, change in body mass index (BMI), change in BMI class, and new diagnoses of diabetes, hypertension, and hyperlipidemia (HLD) during the study period.PLWH switched to TAF (n = 446) demonstrated significantly greater mean increase in weight compared to the control group (n = 162) (1.97 vs 0.88 kg, P = .01), however the effect was only seen in those switched from tenofovir disoproxil fumarate. Those that switched to TAF also had a significantly higher percent increase in weight, increase in BMI, and BMI class. We observed a higher rate of new diagnosis of HLD in the control group compared to the TAF switch group during the study period.PLWH switched to TAF had greater increases in weight after 1 year as compared to those continuing on a TAF free regimen. However, this did not translate to higher rates of obesity related illnesses such as diabetes, hypertension, and HLD during the follow up period

Sun protection behaviors among people living with HIV

People living with HIV (PLWH) are at increased risk for both melanoma and nonmelanoma skin cancers, but there is currently no data on sun protection behaviors among PLWH. We created a 28-question paper survey to collect information on patient demographics and sun protection behaviors among PLWH. We found that although 71.6% of respondents reported spending at least 30 minutes to two hours in the sun daily, only 29.7% reported consistent use of sunscreen. In addition, 41.9% rarely or never received sunscreen counseling by their healthcare providers. There is therefore a need for increased training for healthcare providers in sun protection behavior counseling for PLWH