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Marcadors cel·lulars; Virus de la immunodeficiència humana; Persistència viral Marcadores celulares; Virus de la inmunodeficiencia humana; Persistencia viral Cell markers; Human immunodeficiency virus; Viral persistence Purpose of review To discuss the role of CD4+ T cells with active Human immunodeficiency virus (HIV), meaning infected cells with transcriptional and/or translational viral activity during antiretroviral therapy (ART), focusing on new technologies for its detection, potential cell markers for its characterization, and evidences on the contribution of the active HIV reservoir to long-term viral persistence. Recent findings HIV-infected cells expressing viral ribonucleic acid are systematically detected in subjects on long-term ART. In recent years, powerful new tools have provided significant insights into the nature, quantification, and identification of cells with active HIV, including the identification of new cell markers, and the presence of viral activity in specific cell populations located in different cellular and anatomical compartments. Moreover, studies on viral sequence integrity have identified cell clones with intact viral genomes and active viral transcription that could potentially persist for years. Together, new investigations support the notion that the active reservoir could represent a relevant fraction of long-term infected cells, and therefore, the study of its cell sources and mechanisms of maintenance could represent a significant advance in our understanding of viral persistence and the development of new curative strategies. Summary The presence of HIV-infected cells with viral expression during ART has been traditionally overlooked for years. Based on recent investigations, this active viral reservoir could play an important role in HIV persistence. This work was supported by the Spanish Secretariat of Science and Innovation and FEDER funds (grants SAF2015-67334-R and RTI2018-101082-B-I00 [MINECO/FEDER]), and the Fundació La Marató TV3 (grant 201805-10FMTV3). M.J.B. is supported by the Miguel Servet program funded by the Spanish Health Institute Carlos III (CP17/00179). A.A.-G. is supported by the Spanish Secretariat of Science and Innovation Ph.D. fellowship (BES-2016-076382). The funders had no role in the decision to publish or the preparation of the manuscript.

ADN del VIH-1; Cura del VIH-1; Reservorio de VIH-1 HIV-1 DNA; HIV-1 cure; HIV-1 reservoir ADN del VIH-1; Cura del VIH-1; Reservori del VIH-1 Knowing the mechanisms that govern the persistence of infected CD4+ subpopulations could help us to design new therapies to cure HIV-1 infection. We evaluated the simultaneous distribution of the HIV-1 reservoir in 13 CD4+ subpopulations from 14 HIV-1-infected individuals on antiretroviral therapy to analyze its relationship with HIV-1 transcription, immune activation, and cell proliferation. A unique large blood donation was used to isolate CD4, CD4 resting (CD4r), CD4 activated (CD4a), T naive (TN), T stem cell memory (TSCM), T central memory (TCM), T transitional memory (TTM), T effector memory (TEM), circulating T follicular helper (cTFH), TCD20, TCD32, and resting memory TCD2high (rmTCD2high) cells. HIV-1 DNA measured by droplet digital PCR ranged from 3,636 copies/106 in TTM to 244 in peripheral blood mononuclear cells (PBMCs), with no subpopulation standing out for provirus enrichment. Importantly, all the subpopulations harbored intact provirus by intact provirus DNA assay (IPDA). TCD32, cTFH, and TTM had the highest levels of HIV-1 transcription measured by fluorescent in situ hybridization with flow cytometry (FISH/flow), but without reaching statistical differences. The subpopulations more enriched in provirus had a memory phenotype, were less activated (measured by CD38+/HLA-DR+), and expressed more programmed cell death 1 (PD-1). Conversely, subpopulations transcribing more HIV-1 RNA were not necessarily enriched in provirus and were more activated (measured by CD38+/HLA-DR+) and more proliferative (measured by Ki-67). In conclusion, the HIV reservoir is composed of a mosaic of subpopulations contributing to the HIV-1 persistence through different mechanisms such as susceptibility to infection, provirus intactness, or transcriptional status. The narrow range of reservoir differences between the different blood cell subsets tested suggests limited efficacy in targeting only specific cell subpopulations during HIV-1 cure strategies. IMPORTANCE The main barrier for HIV-1 cure is the presence of latently infected CD4+ T cells. Although various cell subpopulations have been identified as major HIV-1 reservoir cells, the relative contribution of infected CD4 subpopulations in the HIV-1 reservoir remains largely unknown. Here, we evaluated the simultaneous distribution of the HIV-1 reservoir in 13 CD4+ T-cell subpopulations in peripheral blood from HIV-1-infected individuals under suppressive antiretroviral therapy. We found that the HIV-1 reservoir is composed of a mosaic of cell subpopulations, with heterogeneous proviral DNA, HIV-1 transcription, and activation status. Hence, each cell subpopulation contributes to the HIV-1 persistence through different mechanisms such as susceptibility to infection, rates of intact provirus, transcriptional status or half-life. This research provides new insights into the composition of the HIV-1 reservoir, suggesting that, to be effective, eradication strategies must simultaneously target multiple cell subpopulations. This work was sponsored in part by Grifols and by Gilead (GLD17/00204). The funding organizations had no input in the design of the study or in the collection, analyses, and interpretation of the data. Similarly, they played no role in the writing of the manuscript or in the decision to submit the study for publication. J.M.-P. is supported by grant PID2019-109870RB-I00 from the Spanish Ministry of Science and Innovation. J.M.-P. and M.J.B. are supported by the RETIC RD16/0025/0041 and RD16/0025/0007 (cofunded by the European Regional Development Fund/European Social Fund). M.J.B. is supported by grant RTI2018-101082-B-I00 (MINECO/FEDER) and by the Miguel Servet program funded by the Spanish Health Institute Carlos III (CP17/00179). C.G. was supported by the Ph.D. fellowship of the Spanish Ministry of Education, Culture, and Sport (FPU15/03698).

Background: Dysfunction of CD8+ T cells in people living with HIV-1 (PLWH) receiving anti-retroviral therapy (ART) has restricted the efficacy of dendritic cell (DC)-based immunotherapies against HIV-1. Heterogeneous immune exhaustion and metabolic states of CD8+ T cells might differentially associate with dysfunction. However, specific parameters associated to functional restoration of CD8+ T cells after DC treatment have not been investigated. Methods: We studied association of restoration of functional HIV-1-specific CD8+ T cell responses after stimulation with Gag-adjuvant-primed DC with ART duration, exhaustion, metabolic and memory cell subsets profiles. Findings: HIV-1-specific CD8+ T cell responses from a larger proportion of PLWH on long-term ART (more than 10 years; LT-ARTp) improved polyfunctionality and capacity to eliminate autologous p24+ infected CD4+ T cells in vitro. In contrast, functional improvement of CD8+ T cells from PLWH on short-term ART (less than a decade; ST-ARTp) after DC treatment was limited. This was associated with lower frequencies of central memory CD8+ T cells, increased co-expression of PD1 and TIGIT and reduced mitochondrial respiration and glycolysis induction upon TCR activation. In contrast, CD8+ T cells from LT-ARTp showed increased frequencies of TIM3+ PD1− cells and preserved induction of glycolysis. Treatment of dysfunctional CD8+ T cells from ST-ARTp with combined anti-PD1 and anti-TIGIT antibodies plus a glycolysis promoting drug restored their ability to eliminate infected CD4+ T cells. Interpretation: Together, our study identifies specific immunometabolic parameters for different PLWH subgroups potentially useful for future personalized DC-based HIV-1 vaccines. Funding: NIH (R21AI140930), MINECO/FEDER RETOS (RTI2018-097485-A-I00) and CIBERINF grants, NIH (R21AI140930), MINECO/FEDER RETOS (RTI2018-097485-A-I00) and CIBERINF grants

Direct-acting antiviral agents; Opioid Treatment Program; Opioid agonist therapy; Hepatitis C virus infection; Human immunodeficiency virus infection; Drug use Agentes antivirales de acción directa; Programa de Tratamiento de Opioides; Terapia con agonistas opioides; Infección por el virus de la hepatitis C; Infección por el virus de la inmunodeficiencia humana; Uso de drogas Agents antivirals d'acció directa; Programa de tractament amb opioides; Teràpia amb agonistes opioides; Infecció pel virus de l'hepatitis C; Infecció pel virus de la immunodeficiència humana; Ús de drogues Background: Direct-acting antivirals (DAAs) are recommended for the treatment of hepatitis C virus (HCV) infection in patients treated with methadone or buprenorphine. Aim: To assess HCV treatment rates in an Opioid Treatment Program (OTP). Methods: This longitudinal study included 501 patients (81.4% men, median age: 45 years; interquartile range: 39-50 years) enrolled in an OTP between October 2015 and September 2017. Patients were followed until September 2019. Data on socio-demographics, substance use, HCV infection, human immunodeficiency virus (HIV) infection and laboratory parameters were collected at entry. We analyzed medical records to evaluate HCV treatment. Kaplan-Meier methods and Cox regression models were used to analyze the DAA treatment uptake and to identify treatment predictors. Results: Prevalence of HCV and HIV infection was 70% and 34%, respectively. Among anti-HCV-positive (n = 336) patients, 47.2%, 41.3%, and 31.9% used alcohol, cannabis, and cocaine, respectively. HCV-RNA tests were positive in 233 (69.3%) patients. Twentyeight patients (8.3%) cleared the infection, and 59/308 (19.1%) had received interferon-based treatment regimens before 2015. Among 249 patients eligible, 111 (44.6%) received DAAs. Treatment rates significantly increased over time from 7.8/100 person-years (p-y) (95%CI: 5.0-12.3) in 2015 to 18.9/100 p-y (95%CI: 11.7-30.3) in 2019. In a multivariate analysis, patients with HIV co-infection were twice as likely to receive DAAs (HR = 1.94, 95%CI: 1.21-3.12) than patients with HCV mono-infection. Current drug use was an independent risk factor for not receiving treatment against infection (HR = 0.48, 95%CI: 0.29-0.80). Conclusion: HCV treatment is evolving in patients with HCV-HIV co-infection. Ongoing drug use while in an OTP might negatively impact the readiness to treat infection. Supported by the Ministry of Science, Innovation and Universities, Carlos III Health Institute (ISCIII), European Fund for Regional Development (FEDER), Network for Cooperative Research in Health (RETICS), Spain (No. RD16/0017/0003, PI17/00174, INT19/00026, CD19/00019); the Ministry of Health, National Plan on Drugs (PNSD), Spain (No. 2018/020); the European Commission (806996- JUSTSO-JUST2017-AG-DRUG); the Gilead Fellowship Program, Gilead Sciences (No. GLD17/187); the Ministry of Education, Spain (No. PRX18/00245); the Agency for Management of University and Research Grants, Government of Catalonia (No. 2017SGR316); and the Municipal Institute of Personal Services-IMSP, Badalona.

Background and aims Limited data are available on the effectiveness and tolerability of direct-acting antivirals (DAAs) therapies in the real world for HCV-infected patients with comorbidities. This study aimed to describe the effectiveness of OBV/PTV/r +/- DSV (3D/2D regimen) with or without ribavirin (RBV) in HCV or HCV/HIV co-infected patients with GT1/GT4 and CKD (IIIb-V stages), including those under hemodialysis and peritoneal dialysis in routine clinical practice in Spain in 2015. Material and methods Non-interventional, retrospective, multicenter data collection study in 31 Spanish sites. Socio-demographic, clinical variables, study treatment characteristics, effectiveness and tolerability data were collected from medical records. Results Data from 135 patients with a mean age (SD) of 58.3 (11.4) years were analyzed: 92.6% GT1 (81.6% GT1b and 17.6% GT1a) and 7.4% GT4, 14 (10.4%) HIV/HCV co-infected, 19.0% with fibrosis F3 and 28.1% F4 by FibroScan (R), 52.6% were previously treated with pegIFN and RBV. 11.1%, 14.8% and 74.1% of patients had CKD stage IIIb, IV and V respectively. 68.9% of patients were on hemodialysis; 8.9% on peritoneal dialysis and 38.5% had history of renal transplant. A total of 125 (96.2%) of 135 patients were treated with 3D, 10 (7.4%) with 2D and 30.4% received RBV. The overall intention-to-treat (ITT) sustained virologic response at week 12 (SVR12) was 92.6% (125/135) and the overall modified-ITT (mITT) SVR12 was 99.2% (125/126). The SVR12 rates (ITT) per sub-groups were: HCV mono-infected (91.7%), HCV/HIV co-infected (100%), GT1 (92.0%), GT4 (100%), CKD stage IIIb (86.7%), stage IV (95%) and stage V (93%). Among the 10 non-SVR there was only 1 virologic failure (0.7%); 4 patients had missing data due lost to follow up (3.0%) and 5 patients discontinued 3D/2D regimen (3.7%): 4 due to severe adverse events (including 3 deaths) and 1 patient ' s decision. Conclusions These results have shown that 3D/2D regimens are effective and tolerable in patients with advanced CKD including those in dialysis with GT 1 or 4 chronic HCV mono-infection and HIV/HCV coinfection in a real-life cohort. The overall SVR12 rates were 92.6% (ITT) and 99.2% (mITT) without clinically relevant changes in eGFR until 12 weeks post-treatment. These results are consistent with those reported in clinical trials., MCL has served as consultant for AbbVie, MSD, Janssen, BMS and Gilead; MRB has received grant research from Gilead Science, and speaker fees from AbbVie, Gilead and MSD; MR has received speaker fees from AbbVie; MD has received grant support and consultancy fees from AbbVie, Bayer, Bristol-Myers Squibb, Gilead and Merck, Sharp & Dhome; FGR has served as speaker for AbbVie, Gilead and BMS; MLM has served as a speaker for AbbVie, BMS, Gilead, Janssen, MSD and ViiV; as a consultant for AbbVie, BMS and Janssen and has received research funding from FIPSE 36465/03, FIPSE 36680/07.-NEAT IG5 (NEAT is a project funded by the European Union under the 6th Framework programme) contract number LSHP-CT-2006-037570; MAC has served as a consultant for Gilead and and ViiV healthcare, and has received speaker fees from Janssens, Gilead, ViiV Healthcare; MMA reports personal fees from ViiV Healthcare, Gilead Sciences, Merck, Janssen, AbbVie and ABBOTT Laboratories, outside the submitted work; AR has received consultancy and speaker fees from AbbVie, Gilead Sciences and Merck Sharp & Dohme; JM has received honoraria, speaker fees, consultant fees or funds for research from AbbVie, BMS, Boehringer-Ingelheim, Gilead, Janssen, MSD, Roche and ViiV; EGP has received speaker fees from AbbVie and Gilead; LGB has served as consultant for AbbVie and Intercept and has received speaker fees from Gilead and MSD; AA, RMG, CB, TAE, MLG, BPL, IC, SB, LB, JGS, MJP, IMG, LM, IdlS, ML and JEL don't have a financial interest or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this paper; CdA and AM are paid employees of AbbVie and may hold stock or options. The specific roles of these authors are articulated in the 'author contributions' section. The design, study conduct, and financial support for the study were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the manuscript.

VIH; Virus de les Hepatitis; Coinfecció VIH; Virus de las Hepatitis; Coinfección HIV; Hepatitis virus; Coinfection Aquest manual ha estat preparat amb la intenció d'abordar els problemes que planteja el maneig de les persones malaltes amb coinfecció pel virus de la sida i els virus de l'hepatitis. A més, facilita als metges i metgesses assistencials els recursos necessaris per al diagnòstic i la presa de decisions terapèutiques, així com els criteris per ampliar la prevenció en tots aquells grups de població exposats a contraure aquestes infeccions. Este manual ha sido preparado con la intención de abordar los problemas que plantea el manejo de las personas enfermas con coinfección por el virus del sida y los virus de la hepatitis. Además, facilita a los médicos asistenciales los recursos necesarios para el diagnóstico y la toma de decisiones terapéuticas, así como los criterios para ampliar la prevención en todos aquellos grupos de población expuestos a contraer estas infecciones.