DNA methylation landscapes of HIV controllers: an epigenome-wide association study

Cardiovascular Events in the French ANRS HIV Controller Cohort.

Elite controllers (ECs), viraemic controllers (VCs), and long-term nonprogressors (LTNPs) control HIV viral replication or maintain CD4 T-cell counts without antiretroviral therapy, but may have increased cardiovascular disease (CVD) risk compared to HIV-uninfected persons. We evaluated subclinical carotid and coronary atherosclerosis and inflammatory biomarker levels among HIV controllers, LTNPs and noncontrollers and HIV-uninfected individuals in the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS). We measured carotid plaque presence and common carotid artery intima-media thickness (IMT) in 1729 women and 1308 men, and the presence of coronary artery calcium and plaque in a subgroup of men. Associations between HIV control category and carotid and coronary plaque prevalences were assessed by multivariable regression analyses adjusting for demographics and CVD risk factors. Serum inflammatory biomarker concentrations [solubleCD163(sCD163), soluble CD14 (sCD14), galectin-3 (Gal-3), galectin-3binding protein (Gal-3BP) and interleukin (IL)-6] were measured and associations with HIV control category assessed. We included 135 HIV controllers (30 ECs) and 135 LTNPs in the study. Carotid plaque prevalence and carotid IMT were similar in HIV controllers, LTNPs and HIV-uninfected individuals. HIV controllers and LTNPs had lower prevalences of carotid plaque compared to viraemic HIV-infected individuals. The prevalence of coronary atherosclerosis was similar in HIV controllers/LTNPs compared to HIV-uninfected and viraemic HIV-infected men. Controllers and LTNPs had higher concentrations of sCD163 and sCD14 compared to HIV-uninfected persons. Subclinical CVD was similar in HIV controllers, LTNPs and HIV-uninfected individuals despite elevated levels of some inflammatory biomarkers. Future studies of HIV controllers and LTNPs are needed to characterize the risk of CVD among HIV-infected persons.

BackgroundThe HLA-DRB1 gene in the major histocompatibility complex (MHC) region in chromosome 6p21 is the strongest genetic factor identified as influencing multiple sclerosis (MS) susceptibility. DNA methylation changes associated with MS have been consistently detected at the MHC region. However, understanding the full scope of epigenetic regulations of the MHC remains incomplete, due in part to the limited coverage of this region by standard whole genome bisulfite sequencing or array-based methods.MethodsWe developed and validated an MHC capture protocol coupled with bisulfite sequencing and conducted a comprehensive analysis of the MHC methylation landscape in blood samples from 147 treatment naïve MS study participants and 129 healthy controls.ResultsWe identified 132 differentially methylated region (DMRs) within MHC region associated with disease status. The DMRs overlapped with established MS risk loci. Integration of the MHC methylome with human leukocyte antigen (HLA) genetic data indicate that the methylation changes are significantly associated with HLA genotypes. Using DNA methylation quantitative trait loci (mQTL) mapping and the causal inference test (CIT), we identified 643 cis-mQTL-DMRs paired associations, including 71 DMRs possibly mediating causal relationships between 55 single nucleotide polymorphisms (SNPs) and MS risk.ResultsThe results describe MS-associated methylation changes in MHC region and highlight the association between HLA genotypes and methylation changes. Results from the mQTL and CIT analyses provide evidence linking MHC region variations, methylation changes, and disease risk for MS.

Research into the effects of host genetics on HIV disease susceptibility and progression, and on the efficacy and toxicity of drug treatment, occupies a particular position in the landscape of HIV research...

Phenotypic and epigenetic profiles of circulating NK cells in spontaneous HIV-1 controllers

Elite and viremic HIV controllers are able to control their HIV infection and maintain undetectable or low-level viremia in the absence of antiretroviral treatment. Despite extensive studies, the immune factors responsible for such exclusive control remain poorly defined. We identified a cohort of 14 HIV controllers that suffered an abrupt loss of HIV control (LoC) to investigate possible mechanisms and virological and immunological events related to the sudden loss of control. The in-depth analysis of these subjects involved the study of cell tropism of circulating virus, evidence for HIV superinfection, cellular immune responses to HIV, as well as an examination of viral adaptation to host immunity by Gag sequencing. Our data demonstrate that a poor capacity of T cells to mediate in vitro viral suppression, even in the context of protective HLA alleles, predicts a loss of viral control. In addition, the data suggest that inefficient viral control may be explained by an increase of CD8 T-cell activation and exhaustion before LoC. Furthermore, we detected a switch from C5- to X4-tropic viruses in 4 individuals after loss of control, suggesting that tropism shift might also contribute to disease progression in HIV controllers. The significantly reduced inhibition of in vitro viral replication and increased expression of activation and exhaustion markers preceding the abrupt loss of viral control may help identify untreated HIV controllers that are at risk of losing control and may offer a useful tool for monitoring individuals during treatment interruption phases in therapeutic vaccine trials.IMPORTANCE A few individuals can control HIV infection without the need for antiretroviral treatment and are referred to as HIV controllers. We have studied HIV controllers who suddenly lose this ability and present with high in vivo viral replication and decays in their CD4+ T-cell counts to identify potential immune and virological factors that were responsible for initial virus control. We identify in vitro-determined reductions in the ability of CD8 T cells to suppress viral control and the presence of PD-1-expressing CD8+ T cells with a naive immune phenotype as potential predictors of in vivo loss of virus control. The findings could be important for the clinical management of HIV controller individuals, and it may offer an important tool to anticipate viral rebound in individuals in clinical studies that include combination antiretroviral therapy (cART) treatment interruptions and which, if not treated quickly, could pose a significant risk to the trial participants.

Elite controllers (ECs) are an exceptional group of people living with HIV (PLWH) who maintain undetectable viral loads (VLs) despite not being on antiretroviral therapy (ART). However, this phenotype is heterogeneous, with some of these subjects losing virological control over time. In this longitudinal retrospective study, serum acute-phase glycoprotein profile assessed by proton nuclear magnetic resonance (1H-NMR) was determined in 11 transient controllers (TCs) who spontaneously lost virological control and 11 persistent controllers (PCs) who persistently maintained virological control over time. Both PCs and TCs showed similar acute-phase glycoprotein profiles, even when TCs lost the virological control (GlycB, p = 0.824 and GlycA, p = 0.710), and the serum acute-phase glycoprotein signature in PCs did not differ from that in HIV-negative subjects (GlycB, p = 0.151 and GlycA, p = 0.243). Differences in serum glycoproteins A and B were significant only in ECs compared to HIV-typical progressors (TPs) with < 100 CD4+ T-cells (p < 0.001). 1H-NMR acute-phase glycoprotein profile does not distinguish TCs form PCs before the loss of viral control. ECs maintain a low-grade inflammatory state compared to TPs. PCs revealed a closer serum signature to HIV-negative subjects, reaffirming this phenotype as a closer model of functional control of HIV.

Towards addressing questions related to HIV pathogenesis and vaccine design we are fortunate to have the availability of the SIV-infected rhesus macaque model. The strengths of this model which include a rapid rate of progression to AIDS and knowledge of the dose route and strain of the infecting virus complement studies in HIV-infected patients in which the reagents host genetics and access to samples are more extensive and better defined. Unfortunately there is currently still too little known about the antiviral immune responses in either system to directly and accurately compare their similarities and differences and to draw any definitive conclusions. Therefore the data and views presented herein will simply reflect what has recently been discovered in both humans and non-human primate studies. (excerpt)

HIV-1 controllers comprise a heterogeneous group of people living with HIV-1 (PLWH) with the ability to maintain low viral loads and high CD4+ T cell counts for years in the absence of antiretroviral therapy (ART). Within these is a special group of individuals termed "elite controllers" (ECs) who durably maintain undetectable plasma HIV-1 RNA levels without medication. Immune profiles in these rare individuals have been proposed as a model to guide the development of a functional HIV-1 cure. Several protective immune signatures have been linked to better HIV-1 control but host factors described thus far only partly explain effective HIV-1 control (1, 2). In particular, a potent innate immune response is likely critical to contain viral replication early following infection and to promote spontaneous HIV-1 control. Nevertheless, the delineation of innate immune responses in HIV-1 controllers remains an understudied research area. This Research Topic collected contributions advancing progress made on understanding innate immunological mechanisms of spontaneous HIV-1 control and discusses gaps of knowledge and strategies to harness innate immune cells in future immunotherapeutics. Among other roles, innate immune cells coordinate adaptive immune responses and accumulating evidence highlighting that both innate and adaptive arms of the immune response may be responsible for spontaneous control of HIV-1 is beginning to emerge (3, 4) . For instance, in recent reports, myeloid dendritic cells (mDCs) from ECs exhibited increased abilities to sense HIV-1 through cytosolic pathways, consequently enhancing activation of CD8+T cells with a CD64+PD-L1 hi phenotype (5, 6). In the Original Research article by Martin-Gayo et al. the authors identify molecular circuits RNA-sensor RIG-I together with cGAS as key players in mediating the detection of HIV-1 in mDC from ECs. Their findings represent therapeutically actionable pathways for enhancing innate immune responses against HIV-1. Submissions in this Research Topic include four excellent reviews that delve into some of the innate immune mechanisms linked to natural control of HIV-1, starting with a review from Shi et al. which presents an overview of innate immunity as the first line of defense against pathogen invasion and a bridge to induce adaptive immunity. The Frontiers in Immunology frontiersin.org 01

This Month in Genetics

Fine mapping the MHC region identified rs4997052 as a new variant associated with nonobstructive azoospermia in Han Chinese males

Objective To investigate the association between genetic variants in the major histocompatibility complex (MHC) region and gastric cancer (GC) susceptibility. Methods Based on a case-control study, MHC region was imputed with SNP2HLA v1.0.3 software by using the Han-MHC database as a reference panel. Logistic regression analysis model was used to identify the independent genetic loci associated with GC susceptibility in the MHC region. Functional annotation of the MHC region was based on online public databases and performed to find the susceptibility gene and potential functional variants. Results We found that rs2517714 was the only independent association signal associated with GC risk in the MHC region (OR=1.13, P=2.70×10-8). The results of functional annotation showed that HLA amino acid polymorphisms and single nucleotide polymorphisms (SNPs) located in the exon region of HLA-A may affect the stability of HLA-A protein. The SNP rs9295829 located in a non-coding region could remotely regulate the expression of HLA-A by affecting enhancer activity. Conclusion Functional genetic variations in the MHC region may affect the function of the susceptibility gene HLA-A to modulate GC susceptibility.

With obesity on the rise among people living with HIV (PLWH), there is growing concern that weight gain may result as an undesired effect of antiretroviral therapy (ART). This analysis sought to assess the association between ART regimens and changes in body mass index (BMI) among ART-experienced, virologically suppressed PLWH. ART-experienced, virologically suppressed PLWH ≥18 years of age in the Observational Pharmacoepidemiology Research and Analysis (OPERA) cohort were included for analysis if prescribed a new regimen containing one of the following core agents: dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), raltegravir (RAL), rilpivirine (RPV), or boosted darunavir (bDRV), for the first time between August 1, 2013 and December 31, 2017. Multivariable linear regression was used to assess the association between regimen and mean changes in BMI at 6, 12, and 24 months after switch. In unadjusted analyses, BMI increases ranged from 0.30 kg/m2 (bDRV) to 0.83 kg/m2 (RPV) at 24 months following switch, but gains were observed with every regimen. In adjusted analyses, compared to DTG, only bDRV was associated with a smaller increase in BMI at all time points, while EVG/c and RAL were associated with smaller increases in BMI at 6 months only. Overall, results were consistent in analyses stratified by baseline BMI category. BMI increases were relatively small but followed an upward trend over time in this cohort of treatment-experienced, suppressed PLWH. Gains were attenuated with a longer period of follow-up. BMI gains did not differ by regimens, except for bDRV regimens, which were consistently associated with smaller BMI increases than DTG.

Snapshot of clinical studies on people living with HIV in China.

To identify a prognostic factor(s) for patients with chronic hepatitis C (CHC), we conducted a genome-wide association study (GWAS) using 682 hepatitis C virus (HCV)-induced liver cirrhosis (LC) cases and 1,045 CHC patients in Japan. Eight SNPs which showed possible associations (P &amp;lt; 1.0 x 10-5) in the GWAS stage were further genotyped using 936 LC cases and 3,809 CHC patients. We found that two SNPs within the major histocompatibility complex (MHC) region on chromosome 6p21, rs910049 and rs3135363, were significantly associated with the progression from CHC to LC (Pcombined = 9.15 x 10-11 and 1.45 x 10-10, odds ratio (OR) = 1.46 and 1.37, respectively). We also found that HLA-DQA1*0601 and HLA-DRB1*0405 were associated with progression from CHC to LC (P = 4.53 x 10-4 and 1.54 x 10-4 with OR = 2.80 and 1.45, respectively). Multiple logistic regression analysis revealed that rs3135363, rs910049, and HLA-DQA1*0601 were independently associated with the risk of HCV-induced LC. In addition, individuals with four or more risk alleles for these three loci have a 2.83-fold higher risk for LC than those with no risk allele, indicating the cumulative effects of these variations. Our findings elucidated the crucial roles of multiple genetic variations within the MHC region as prognostic/predictive biomarkers for CHC patients. Citation Format: Matsuda Koichi, Chizu Tanikawa, Yusuke Nakamura. A genome-wide association study of HCV induced liver cirrhosis in the Japanese population identifies novel susceptibility loci at MHC region. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2551. doi:10.1158/1538-7445.AM2013-2551