P21^WAF1/CIP1 RNA expression in highly HIV-1 exposed, uninfected individuals

Some individuals remain HIV-1 antibody and PCR negative after repeated exposures to the virus, and are referred to as HIV-exposed seronegatives (HESN). However, the causes of resistance to HIV-1 infection in cases other than those with a homozygous CCR5Δ32 deletion are unclear. We hypothesized that human p21WAF1/CIP1 (a cyclin-dependent kinase inhibitor) could play a role in resistance to HIV-1 infection in HESN, as p21 expression has been associated with suppression of HIV-1 in elite controllers and reported to block HIV-1 integration in cell culture. We measured p21 RNA expression in PBMC from 40 HESN and 40 low exposure HIV-1 seroconverters (LESC) prior to their infection using a real-time PCR assay. Comparing the 20 HESN with the highest exposure risk (median = 111 partners/2.5 years prior to the 20 LESC with the lowest exposure risk (median = 1 partner/2.5 years prior), p21 expression trended higher in HESN in only one of two experiments (P = 0.11 vs. P = 0.80). Additionally, comparison of p21 expression in the top 40 HESN (median = 73 partners/year) and lowest 40 LESC (median = 2 partners/year) showed no difference between the groups (P = 0.84). There was a weak linear trend between risk of infection after exposure and increasing p21 gene expression (R2 = 0.02, P = 0.12), but again only in one experiment. Hence, if p21 expression contributes to the resistance to viral infection in HESN, it likely plays a minor role evident only in those with extremely high levels of exposure to HIV-1

Fat distribution and longitudinal anthropometric changes in HIV-infected men with and without clinical evidence of lipodystrophy and HIV-uninfected controls: A substudy of the Multicenter AIDS Cohort Study

<p>Abstract</p> <p>Background</p> <p>Fat abnormalities are common among HIV-infected persons, but few studies have compared regional body fat distribution, including visceral fat, in HIV-infected and HIV-uninfected persons and their subsequent trajectories in body composition over time.</p> <p>Methods</p> <p>Between 1999 and 2002, 33 men with clinical evidence of lipodystrophy (LIPO+), 23 HIV-infected men without clinical evidence of lipodytrophy (LIPO-), and 33 HIV-uninfected men were recruited from the four sites of the Multicenter AIDS Cohort Study (MACS). Participants underwent dual-energy x-ray absorptiometry, quantitative computerized tomography of the abdomen and thigh, and circumference measurements of the waist, hip and thigh. Circumference measurements at each semi-annual MACS visit between recruitment and 2008 were used to compare average annual anthropometric changes in the 3 groups.</p> <p>Results</p> <p>Body mass index (BMI) was lower in LIPO+ men than in the LIPO- men and the HIV- uninfected controls (BMI: 23.6 ± 0.4 vs 26.8 ± 1.5 vs 28.7 ± 0.9 kg/m², respectively, p < 0.001). The average amount of visceral adipose tissue (VAT) was similar in all three groups (p = 0.26), but after adjustment for BMI, VAT was higher in the LIPO+ group (169 ± 10 cm²) compared to the LIPO- men (129 ± 12 cm², p = 0.03) and the HIV-uninfected group (133 ± 11 cm², p = 0.07). Subcutaneous adipose tissue (thigh, abdomen) and total extremity fat were less in the HIV-infected men (LIPO+ and LIPO-) than in the HIV-uninfected men. Over an average of 6 years of follow-up, waist circumference increased at a faster rate in LIPO+ group, compared to the LIPO- men (0.51 cm/year vs 0.08 cm/year, p = 0.02) and HIV-uninfected control men (0.21 cm/year, p = 0.06). The annual changes in hip and thigh circumferences were similar in all three groups</p> <p>Conclusion</p> <p>Subcutaneous lipoatrophy was observed in HIV-infected patients, even those without clinical evidence of lipodystrophy, compared to age-matched HIV-uninfected men. Despite markedly lower BMI, HIV-infected men with lipodystrophy had a similar amount of VAT as HIV-uninfected men and tended to have more rapid increases in waist circumference over 6 years of follow-up. These longitudinal increases in waist circumference may contribute to the development of cardiovascular risk in HIV-infected patients with lipodystrophy.</p

Long-Term Kidney Function, Proteinuria, and Associated Risks among HIV-Infected and Uninfected Men in the MACS

Background: Factors affecting kidney function and proteinuria among HIV-positive (HIV+) and HIV-negative (HIV–) persons need better characterization. Methods: We evaluated estimated glomerular filtration rate (eGFR, ml/min per 1.73 m2) changes, proteinuria prevalence (a urine protein-to-creatinine ratio of ≥0.2 at two consecutive visits) and associated factors among HIV+ and HIV− men. Results: There were 917 HIV+ men receiving HAART, 159 HIV+ men not receiving HAART, and 1305 HIV− men seen from October 2003 to September 2014. Median annual eGFR change was −0.5, −0.8% for HIV+ and −0.3% for HIV− men (P < 0.001). Factors significantly (P < 0.05) associated with more than 3% annual eGFR decline were HAART receipt (but no specific antiretroviral drug), age more than 50, hypertension, diabetes, current smoking. Proteinuria existed in 14.9% of visit-pairs among HAART recipients, 5.8% among non-HAART recipients, and 1.9% among HIV− men, and was associated with subsequent annual more than 3% eGFR decline (odds ratio 1.80, P < 0.001). Proteinuria-associated factors also included HAART use (vs. HIV−), age at least 50 (vs. <40), diabetes, hypertension, current smoking, hepatitis C virus-infection (all P < 0.05) and, among HIV+ men, lower CD4+ cell count, didanosine, saquinavir, or nelfinavir use (all P < 0.05). After adjusting for proteinuria, among HAART users, having a detectable HIV RNA, cumulative use of tenofovir disoproxil fumarate, emtricitabine, ritonavir, atazanavir, any protease inhibitor, or fluconazole were associated with more than 3% annual eGFR decline. Conclusion: Longitudinal kidney function decline was associated with HAART use but no individual antiretroviral drug, and traditional kidney disease risks. Proteinuria was nearly seven times more common in HAART-treated men than HIV− men, reflected recent eGFR decline and predicted subsequent eGFR declin

A quantitative approach for measuring the reservoir of latent HIV-1 proviruses.

A stable latent reservoir for HIV-1 in resting CD4+ T cells is the principal barrier to a cure1-3. Curative strategies that target the reservoir are being tested4,5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays for cells that release infectious virus after one round of T cell activation1. However, these quantitative outgrowth assays and newer assays for cells that produce viral RNA after activation6 may underestimate the reservoir size because one round of activation does not induce all proviruses7. Many studies rely on simple assays based on polymerase chain reaction to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority of proviruses are defective7-9. Here we describe a more accurate method of measuring the HIV-1 reservoir that separately quantifies intact and defective proviruses. We show that the dynamics of cells that carry intact and defective proviruses are different in vitro and in vivo. These findings have implications for targeting the intact proviruses that are a barrier to curing HIV infection

JC Virus Antibody and Viremia as Predictors of Progressive Multifocal Leukoencephalopathy in Human Immunodeficiency Virus-1-Infected Individuals

We examined whether prediagnostic John Cunningham virus (JCV) antibodies and viremia are predictors of progressive multifocal leukoencephalopathy (PML) in 83 PML cases and 240 human immunodeficiency virus (HIV) disease-matched controls. JCV viremia was not predictive of PML, but some patients showed higher anti-JCV immunoglobulin G (IgG) responses 6 months prior to diagnosi

CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome.

Multiple genome-wide studies have identified associations between outcome of human immunodeficiency virus (HIV) infection and polymorphisms in and around the gene encoding the HIV co-receptor CCR5, but the functional basis for the strongest of these associations, rs1015164A/G, is unknown. We found that rs1015164 marks variation in an activating transcription factor 1 binding site that controls expression of the antisense long noncoding RNA (lncRNA) CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4+ T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3' untranslated region, protecting CCR5 messenger RNA from Raly-mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4+ T cells with CCR5-tropic HIV in vitro. These data represent a rare determination of the functional importance of a genome-wide disease association where expression of a lncRNA affects HIV infection and disease progression

Weight gain among treatment-naïve persons with HIV starting integrase inhibitors compared to non-nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada.

IntroductionWeight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio-metabolic disease. We assessed relationships between ART drug class and weight change among treatment-naïve PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).MethodsAdult, treatment-naïve PWH in NA-ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV-1 RNA level and CD4+ cell count. Due to shorter follow-up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with &gt;10% weight gain at two and five years.ResultsAmong 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI-, 31% started PI- and 20% started INSTI-based regimens (1624 raltegravir (RAL), 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI-based regimens had mean estimated five-year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two-year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline CD4+ cell counts, and those initiating INSTI-based regimens had higher odds of &gt;10% body weight increase at two years (adjusted odds ratio&nbsp;=&nbsp;1.37, 95% confidence interval: 1.20 to 1.56 vs. NNRTI).ConclusionsPWH initiating INSTI-based regimens gained, on average, more weight compared to NNRTI-based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration

The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts

Objective: To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART). Design: Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women's Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively. Methods: Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era. Results: Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2-2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3-1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8-2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02-8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3-1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5-2.4; p<0.001). Conclusion: HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality. © 2013 Gingo et al

Constructing a climate change logic: An institutional perspective on the "tragedy of the commons"

Despite increasing interest in transnational fields, transnational commons have received little attention. In contrast to economic models of commons, which argue that commons occur naturally and are prone to collective inaction and tragedy, we introduce a social constructionist account of commons. Specifically, we show that actor-level frame changes can eventually lead to the emergence of an overarching, hybrid "commons logic" at the field level. These frame shifts enable actors with different logics to reach a working consensus and avoid "tragedies of the commons." Using a longitudinal analysis of key actors' logics and frames, we tracked the evolution of the global climate change field over 40 years. We bracketed time periods demarcated by key field-configuring events, documented the different frame shifts in each time period, and identified five mechanisms (collective theorizing, issue linkage, active learning, legitimacy seeking, and catalytic amplification) that underpin how and why actors changed their frames at various points in time-enabling them to move toward greater consensus around a transnational commons logic. In conclusion, the emergence of a commons logic in a transnational field is a nonlinear process and involves satisfying three conditions: (1) key actors view their fates as being interconnected with respect to a problem issue, (2) these actors perceive their own behavior as contributing to the problem, and (3) they take collective action to address the problem. Our findings provide insights for multinational companies, nation-states, nongovernmental organizations, and other stakeholders in both conventional and unconventional commons