Approximately 25% of elite controllers (ECs) lose their virological control by mechanisms that are only partially known. Recently, immunovirological and proteomic factors have been associated to the loss of spontaneous control. Our aim was to perform a metabolomic approach to identify the underlying mechanistic pathways and potential biomarkers associated with this loss of control. Plasma samples from EC who spontaneously lost virological control (Transient Controllers, TC, n = 8), at two and one year before the loss of control, were compared with a control group of EC who persistently maintained virological control during the same follow-up period (Persistent Controllers, PC, n = 8). The determination of metabolites and plasma lipids was performed by GC-qTOF and LC-qTOF using targeted and untargeted approaches. Metabolite levels were associated with the polyfunctionality of HIV-specific CD8+T-cell response. Our data suggest that, before the loss of control, TCs showed a specific circulating metabolomic profile characterized by aerobic glycolytic metabolism, deregulated mitochondrial function, oxidative stress and increased immunological activation. In addition, CD8+ T-cell polyfunctionality was strongly associated with metabolite levels. Finally, valine was the main differentiating factor between TCs and PCs. All these metabolomic differences should be considered not only as potential biomarkers but also as therapeutic targets in HIV infection. FUND: This work was supported by grants from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Fondos FEDER; Red de Investigación en Sida, Gilead Fellowship program, Spanish Ministry of Education and Spanish Ministry of Economy and Competitiveness.

Poor immunological recovery in treated HIV-infected patients is associated with greater morbidity and mortality. To date, predictive biomarkers of this incomplete immune reconstitution have not been established. We aimed to identify a baseline metabolomic signature associated with a poor immunological recovery after ART in order to envisage the underlying mechanistic pathways that influence the treatment response. This was a multi-centre, prospective cohort study in ART–naïve and a pre-ART low nadir (<200 cells/μl) HIV-infected patients (n = 64). We obtained clinical data and metabolomic profiles for each individual, in which low molecular weight metabolites, lipids and lipoproteins (including particle concentrations and sizes) were measured by nuclear magnetic resonance spectroscopy. Immunological recovery was defined as reaching CD4+ T-cell count ≥250 cells/μL after 36 months of virologically successful ART. We used univariate comparisons, Random Forest test and ROC curves to identify and evaluate the predictive factors of immunological recovery after treatment. HIV-infected patients with a baseline metabolic pattern characterized by high levels of large HDL particles, HDL cholesterol and larger sizes of LDL particles had a better immunological recovery after treatment. Conversely, patients with high ratios of non HDL lipoprotein particles did not experience this full recovery. Medium VLDL particles and glucose increased the classification power of the multivariate model despite not showing any significant differences between the two groups. In HIV-infected patients, a baseline healthier metabolomic profile is related to a better response to ART where the lipoprotein profile, mainly large HDL particles, may play a key role.

Background. The purpose of this study was to assess the prevalence of anti-hepatitis C virus (HCV) antibodies (Abs) and active HCV infection in human immunodeficiency virus (HIV)-infected (HIV+) patients in Spain in 2015. This was a cross-sectional study. Methods. The study was performed in 41 centers in 2015. Sample size was estimated for an accuracy of 2%, the number of patients from each hospital was determined by proportional allocation, and patients were selected using simple random sampling. Results. The reference population was 35 791 patients, and the sample size was 1867 patients. Hepatitis C virus serostatus was known in 1843 patients (98.7%). Hepatitis C virus-Abs were detected in 695 patients (37.7%), in whom the main route of HIV acquisition was injection drug use (75.4%). Of these 695 patients, 402 had HCV RNA, 170 had had a sustained viral response (SVR) after anti-HCV therapy, and 102 cleared HCV spontaneously. Hepatitis C virus-ribonucleic acid results were unknown in 21 cases. Genotype distribution (known in 367 patients) was 1a in 143 patients (39.0%), 4 in 90 (24.5%) patients, 1b in 69 (18.8%) patients, 3 in 57 (15.5%) patients, 2 in 5 (1.4%) patients, and mixed in 3 (0.8%) patients. Liver cirrhosis was present in 93 patients (23.1%) with active HCV infection and in 39 (22.9%) patients with SVR after anti-HCV therapy. Conclusions. The prevalence of HCV-Abs and active HCV infection in HIV+ patients in Spain is 37.7% and 22.1%, respectively; these figures are significantly lower than those recorded in 2002 and 2009. The predominant genotypes in patients with active HCV infection were 1a and 4. A high percentage of patients had cirrhosis. Cirrhosis is also common in patients with SVR after anti-HCV therapy.

Elite controllers (ECs) spontaneously control plasma human immunodeficiency virus type 1 (HIV-1) RNA without antiretroviral therapy. However, 25% lose virological control over time. The aim of this work was to study the proteomic profile that preceded this loss of virological control to identify potential biomarkers. Plasma samples from ECs who spontaneously lost virological control (transient controllers [TCs]), at 2 years and 1 year before the loss of control, were compared with a control group of ECs who persistently maintained virological control during the same follow-up period (persistent controllers [PCs]). Comparative plasma shotgun proteomics was performed with tandem mass tag (TMT) isobaric tag labeling and nanoflow liquid chromatography coupled to Orbitrap mass spectrometry. Eighteen proteins exhibited differences comparing PC and preloss TC timepoints. These proteins were involved in proinflammatory mechanisms, and some of them play a role in HIV-1 replication and pathogenesis and interact with structural viral proteins. Coagulation factor XI, α-1-antichymotrypsin, ficolin-2, 14-3-3 protein, and galectin-3-binding protein were considered potential biomarkers. The proteomic signature associated with the spontaneous loss of virological control was characterized by higher levels of inflammation, transendothelial migration, and coagulation. Galectin-3 binding protein could be considered as potential biomarker for the prediction of virological progression and as therapeutic target in ECs.

Background: HIV-1 can induce disturbances in adipose tissue in infected subjects through the effects of some of its proteins or inflammation. It is not known whether this also takes place in HIV-1–infected long-term nonprogressors (LTNPs). Our objectives were to determine whether adipocyte differentiation/lipid, inflammatory, and mitochondrial parameters are perturbed in abdominal wall subcutaneous adipose tissue of untreated HIV-1–infected patients LTNPs. Methods: Cross-sectional study involving 10 LTNPs, 10 typical progressors (TPs), and 10 uninfected controls (UCs). The parameters assessed were peroxisome proliferator–activated receptor-gamma (PPARγ), lipoprotein lipase, and fatty acid–binding protein 4 mRNA (adipogenic/lipid); tumor necrosis factor-alpha, interleukin 18 (IL-18), β2-MCG, monocyte chemoattractant protein 1, CD1A, and C3 mRNA (inflammation); and cytochrome c oxidase subunit II (COII), COIV, CYCA, nuclear respiratory factor 1, PPARγ coactivator 1α mRNA, and mtDNA content (mitochondrial). Results: Regarding adipogenic/lipid parameters, LTNPs had PPARγ, lipoprotein lipase, and fatty acid–binding protein 4 mRNA significantly decreased compared with UCs (P ≤ 0.001 for all comparisons). PPARγ mRNA was significantly greater in LTNP than in TP (P = 0.006). With respect to inflammatory parameters, tumor necrosis factor-alpha, IL-18, and β2-MCG mRNA were significantly higher in LTNPs compared with UCs (P < 0.005 for all comparisons), whereas IL-18 mRNA was greater in TPs compared with LTNPs (P = 0.01). As mitochondrial parameters are concerned, mtDNA was significantly reduced in LTNPs compared with TPs (P = 0.04) and UCs (P = 0.03). COII and COIV were also significantly reduced in LTNPs compared with UCs and TPs. Conclusions: Adipose tissue from untreated LTNPs may have limited but significant derangements in some adipogenic/lipid and may have inflammatory processes at a lower degree than that observed in untreated TPs. LTNPs may have mitochondrial-related alterations in adipose tissue which are greater than that observed in TPs.