HIV-1 Nef Targets HDAC6 to Assure Viral Production and Virus Infection

HIV Nef is a central auxiliary protein in HIV infection and pathogenesis. Our results indicate that HDAC6 promotes the aggresome/autophagic degradation of the viral polyprotein Pr55Gag to inhibit HIV-1 production. Nef counteracts this antiviral activity of HDAC6 by inducing its degradation and subsequently stabilizing Pr55Gag and Vif viral proteins. Nef appears to neutralize HDAC6 by an acidic/endosomal-lysosomal processing and does not need the downregulation function, since data obtained with the non-associated cell-surface Nef-G2A mutant – the cytoplasmic location of HDAC6 – together with studies with chemical inhibitors and other Nef mutants, point to this direction. Hence, the polyproline rich region P72xxP75 (69–77 aa) and the di-Leucin motif in the Nef-ExxxLL160-165 sequence of Nef, appear to be responsible for HDAC6 clearance and, therefore, required for this novel Nef proviral function. Nef and Nef-G2A co-immunoprecipitate with HDAC6, whereas the Nef-PPAA mutant showed a reduced interaction with the anti-HIV-1 enzyme. Thus, the P72xxP75 motif appears to be responsible, directly or indirectly, for the interaction of Nef with HDAC6. Remarkably, by neutralizing HDAC6, Nef assures Pr55Gag location and aggregation at plasma membrane, as observed by TIRFM, promotes viral egress, and enhances the infectivity of viral particles. Consequently, our results suggest that HDAC6 acts as an anti-HIV-1 restriction factor, limiting viral production and infection by targeting Pr55Gag and Vif. This function is counteracted by functional HIV-1 Nef, in order to assure viral production and infection capacities. The interplay between HIV-1 Nef and cellular HDAC6 may determine viral infection and pathogenesis, representing both molecules as key targets to battling HIV

Contribution of the HIV-1 Envelope Glycoprotein to AIDS Pathogenesis and Clinical Progression

In the absence of antiviral therapy, HIV-1 infection progresses to a wide spectrum of clinical manifestations that are the result of an entangled contribution of host, immune and viral factors. The contribution of these factors is not completely established. Several investigations have described the involvement of the immune system in the viral control. In addition, distinct HLA-B alleles, HLA-B27, -B57-58, were associated with infection control. The combination of these elements and antiviral host restriction factors results in different clinical outcomes. The role of the viral proteins in HIV-1 infection has been, however, less investigated. We will review contributions dedicated to the pathogenesis of HIV-1 infection focusing on studies identifying the function of the viral envelope glycoprotein (Env) in the clinical progression because of its essential role in the initial events of the virus life-cycle. Some analysis showed that inefficient viral Envs were dominant in non-progressor individuals. These poorly-functional viral proteins resulted in lower cellular activation, viral replication and minor viral loads. This limited viral antigenic production allows a better immune response and a lower immune exhaustion. Thus, the properties of HIV-1 Env are significant in the clinical outcome of the HIV-1 infection and AIDS pathogenesis.This work was funded by the Spanish AIDS network “Red Temática Cooperativa de Investigación en SIDA” RD12/0017/0002, RD12/0017/0028, RD12/0017/0034, RD16/0025/0011, RDCIII16/0002/0005 and RD16/0025/0041 as part of the Plan Nacional R + D+I and co-funded by the Spanish “Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER)”. J.B. is a researcher from “Fundació Institut de Recerca en Ciències de la Salut Germans Trias i Pujol” supported by the Health Department of the Catalonian Government/Generalitat de Catalunya and ISCIII grant Nos. PI17/01318 and PI20/00093 (to J.B.). Work in C.C. Lab was supported by grants SAF (2010-17226) and (2016-77894-R) from MINECO (Spain), FIS (PI13/02269, ISCIII) and PI20/00093. A.-V.F.’s Lab is supported by the European Regional Development Fund (ERDF), PID2021-123031OB-I00 (“Ministerio de Ciencia e Innovación”, Spain), RTI2018-093747-B-100 (“Ministerio de Ciencia, Innovación y Universidades”, Spain), ProID2020010093 (“Agencia Canaria de Investigación, Innovación y Sociedad de la Información” and the European Social Fund), UNLL10-3E-783 (ERDF and “Fundación CajaCanarias”) and “SEGAI-ULL”. S.-P.Y. is funded by “Fundación Doctor Manuel Morales” (La Palma, Spain) and “Contrato Pre-doctoral Ministerio-ULL Formación de Doctores” (2019 Program) (“Ministerio de Ciencia, Innovación y Universidades”, Spain). R.-C.R. is funded by RD16/0025/0011 and ProID2020010093 (“Agencia Canaria de Investigación, Innovación y Sociedad de la Información” and European Social Fund). J.-G.L. is funded by the “Juan de la Cierva de Incorporación” Spanish Program (IJC2019-038902-I) (“Ayudas Juan de la Cierva de incorporación; Agencia Estatal de Investigación. Ministerio de Ciencia e Innovación”).S

The Characteristics of the HIV-1 Env Glycoprotein Are Linked With Viral Pathogenesis

The understanding of HIV-1 pathogenesis and clinical progression is incomplete due to the variable contribution of host, immune, and viral factors. The involvement of viral factors has been investigated in extreme clinical phenotypes from rapid progressors to long-term non-progressors (LTNPs). Among HIV-1 proteins, the envelope glycoprotein complex (Env) has been concentrated on in many studies for its important role in the immune response and in the first steps of viral replication. In this study, we analyzed the contribution of 41 Envs from 24 patients with different clinical progression rates and viral loads (VLs), LTNP-Elite Controllers (LTNP-ECs); Viremic LTNPs (vLTNPs), and non-controller individuals contemporary to LTNPs or recent, named Old and Modern progressors. We studied the Env expression, the fusion and cell-to-cell transfer capacities, as well as viral infectivity. The sequence and phylogenetic analysis of Envs were also performed. In every functional characteristic, the Envs from subjects with viral control (LTNP-ECs and vLTNPs) showed significant lower performance compared to those from the progressor individuals (Old and Modern). Regarding sequence analysis, the variable loops of the gp120 subunit of the Env (i.e., V2, V4, and mainly V5) of the progressor individuals showed longer and more glycosylated sequences than controller subjects. Therefore, HIV-1 Envs from virus of patients presenting viremic control and the non-progressor clinical phenotype showed poor viral functions and shorter sequences, whereas functional Envs were associated with virus of patients lacking virological control and with progressor clinical phenotypes. These correlations support the role of Env genotypic and phenotypic characteristics in the in vivo HIV-1 infection and pathogenesis.This work is supported by Spanish AIDS network “Red Temática Cooperativa de Investigación en SIDA” RD12/0017/0002, RD12/0017/0028, RD12/0017/0034, RD16/0025/0011, RDCIII16/0002/0005, and RD16/0025/0041 as part of the Plan Nacional R + D + I and cofunded by Spanish “Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER).” JB is a researcher from “Fundació Institut de Recerca en Ciències de la Salut Germans Trias i Pujol” supported by the Health Department of the Catalan Government/Generalitat de Catalunya and ISCIII grant numbers PI17/01318 and PI20/00093 (to JB). Work in CL-G and CC lab was supported by grants SAF (2010-17226) and (2016-77894-R) from MINECO (Spain) and FIS (PI 13/02269 and PI20/00093, ISCIII). AV-F’s Lab is supported by the European Regional Development Fund (ERDF), RTI2018-093747-B-100 (“Ministerio de Ciencia e Innovación,” Spain), “Ministerio de Ciencia, Innovación y Universidades” (Spain), ProID2020010093 (“Agencia Canaria de Investigación, Innovación y Sociedad de la Información” and European Social Fund), UNLL10-3E-783 (ERDF and “Fundación CajaCanarias”) and “SEGAI-ULL.” SP-Y is funded by “Fundación Doctor Manuel Morales” (La Palma, Spain) and “Contrato Predoctoral Ministerio-ULL Formación de Doctores” (2019 Program; “Ministerio de Ciencia, Innovación y Universidades,” Spain). RC-R is funded by RD16/0025/0011 and ProID2020010093 (“Agencia Canaria de Investigación, Innovación y Sociedad de la Información” and European Social Fund). JE-H is funded by the Cabildo Tenerife “Agustin de Betancourt” 2017 Program.S

HIV-1 envelope glycoproteins isolated from viremic non-progressor individuals are fully functional and cytopathic

International audienc

Transactive Response DNA-Binding Protein (TARDBP/TDP-43) Regulates Cell Permissivity to HIV-1 Infection by Acting on HDAC6

The transactive response DNA-binding protein (TARDBP/TDP-43) influences the processing of diverse transcripts, including that of histone deacetylase 6 (HDAC6). Here, we assessed TDP-43 activity in terms of regulating CD4+ T-cell permissivity to HIV-1 infection. We observed that overexpression of wt-TDP-43 increased both mRNA and protein levels of HDAC6, resulting in impaired HIV-1 infection independently of the viral envelope glycoprotein complex (Env) tropism. Consistently, using an HIV-1 Env-mediated cell-to-cell fusion model, the overexpression of TDP-43 levels negatively affected viral Env fusion capacity. Silencing of endogenous TDP-43 significantly decreased HDAC6 levels and increased the fusogenic and infection activities of the HIV-1 Env. Using pseudovirus bearing primary viral Envs from HIV-1 individuals, overexpression of wt-TDP-43 strongly reduced the infection activity of Envs from viremic non-progressors (VNP) and rapid progressors (RP) patients down to the levels of the inefficient HIV-1 Envs observed in long-term non-progressor elite controllers (LTNP-EC). On the contrary, silencing endogenous TDP-43 significantly favored the infectivity of primary Envs from VNP and RP individuals, and notably increased the infection of those from LTNP-EC. Taken together, our results indicate that TDP-43 shapes cell permissivity to HIV-1 infection, affecting viral Env fusion and infection capacities by altering the HDAC6 levels and associated tubulin-deacetylase anti-HIV-1 activity.This work is supported by the Spanish AIDS network “Red Temática Cooperativa de Investigación en SIDA” RD12/0017/0002, RD12/0017/0028, RD12/0017/0034, RD16/0025/0011, RDCIII16/0002/0005 and RD16/0025/0041 as part of the Plan Nacional R + D+I and co-funded by the Spanish “Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER)”. J.B. is a researcher from “Fundació Institut de Recerca en Ciències de la Salut Germans Trias i Pujol” supported by the Health Department of the Catalonian Government/Generalitat de Catalunya and ISCIII grant numbers PI17/01318 and PI20/00093 (to J.B.). Work in CC Lab was supported by grants SAF (2010-17226) and (2016-77894-R) from MINECO (Spain), FIS (PI 13/02269, ISCIII) and PI20/00093. Work in CF Lab was supported by the Cabildo Insular de Tenerife (grants CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”); the agreement with the Instituto Tecnológico y de Energías Renovables (ITER) to strengthen scientific and technological education, training research, development and innovation in Genomics, Personalized Medicine and Biotechnology (grant number OA17/008). A.V.-F.’s Lab is supported by the European Regional Development Fund (ERDF), RTI2018-093747-B-100 (“Ministerio de Ciencia e Innovación”, Spain), “Ministerio de Ciencia, Innovación y Universidades” (Spain), ProID2020010093 (“Agencia Canaria de Investigación, Innovación y Sociedad de la Información” and European Social Fund), UNLL10-3E-783 (ERDF and “Fundación CajaCanarias”) and “SEGAI-ULL”. S.P-Y is funded by “Fundación Doctor Manuel Morales” (La Palma, Spain) and “Contrato Predoctoral Ministerio-ULL Formación de Doctores” (2019 Program) (“Ministerio de Ciencia, Innovación y Universidades”, Spain). R.C.-R. is funded by RD16/0025/0011 and ProID2020010093 (“Agencia Canaria de Investigación, Innovación y Sociedad de la Información” and European Social Fund). J.G.-L. is funded by the “Juan de la Cierva de Incorporación” Spanish Program (IJC2019-038902-I) (“Ayudas Juan de la Cierva de incorporación; Agencia Estatal de Investigación. Ministerio de Ciencia e Innovación”).S

Aportes desde la extensión para revalorizar la ciencia en las escuelas

Este trabajo describe una intervención educativa que se llevó a cabo en el marco del Proyecto de Extensión “La Facultad va a la Escuela del Barrio” de la UNLP con un grupo de escuelas rurales próximas a la ciudad de La Plata. Nuestro objetivo es contribuir a mejorar la enseñanza de las Ciencias Naturales en el nivel primario utilizando la experimentación como herramienta didáctica. La intervención se basó en una perspectiva reflexiva y se centró en la realización de talleres junto a los docentes, basados en la currícula escolar e incluyó tanto una planificación como una evaluación conjunta. Los talleres se constituyeron en un dispositivo analizador, no sólo de conocimientos teóricos, sino también de las prácticas docentes. La intervención apostó a que el docente se apropie de metodologías científicas y revalorice el conocimiento científico, principalmente en estas instituciones cuya comunidad se encuentra inmersa en una dura realidad socioeconómica. La constitución interdisciplinaria del grupo permitió responder a las inquietudes de las maestras, las cuáles abarcaron varias disciplinas. A partir de la evaluación se rescataron los siguientes indicadores: el impacto positivo que produce la implementación en el aula; la adquisición de equipamiento de laboratorio por parte de las escuelas; el efecto multiplicador hacia otras instituciones, nuestra incorporación al Proyecto Institucional.Facultad de Humanidades y Ciencias de la Educació

Aportes desde la extensión para revalorizar la ciencia en las escuelas

Este trabajo describe una intervención educativa que se llevó a cabo en el marco del Proyecto de Extensión “La Facultad va a la Escuela del Barrio” de la UNLP con un grupo de escuelas rurales próximas a la ciudad de La Plata. Nuestro objetivo es contribuir a mejorar la enseñanza de las Ciencias Naturales en el nivel primario utilizando la experimentación como herramienta didáctica. La intervención se basó en una perspectiva reflexiva y se centró en la realización de talleres junto a los docentes, basados en la currícula escolar e incluyó tanto una planificación como una evaluación conjunta. Los talleres se constituyeron en un dispositivo analizador, no sólo de conocimientos teóricos, sino también de las prácticas docentes. La intervención apostó a que el docente se apropie de metodologías científicas y revalorice el conocimiento científico, principalmente en estas instituciones cuya comunidad se encuentra inmersa en una dura realidad socioeconómica. La constitución interdisciplinaria del grupo permitió responder a las inquietudes de las maestras, las cuáles abarcaron varias disciplinas. A partir de la evaluación se rescataron los siguientes indicadores: el impacto positivo que produce la implementación en el aula; la adquisición de equipamiento de laboratorio por parte de las escuelas; el efecto multiplicador hacia otras instituciones, nuestra incorporación al Proyecto Institucional.Facultad de Humanidades y Ciencias de la Educació

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Estudio de factores que puedan regular la actividad antiviral de HDAC6, y efecto sobre la capacidad proviral del complejo de envoltura de virus primarios de pacientes VIH+

Programa de doctorado en Ciencias de la Salud por la Universidad de La LagunaEl VIH/SIDA sigue siendo una amenaza global, a pesar de los notables esfuerzos realizados por las comunidades científica y sanitaria para comprender la infección viral, el diseño de nuevos fármacos o la mejora de los existentes, así como del desarrollo de terapias avanzadas y diseño de potenciales vacunas para lograr la cura funcional y la erradicación viral. La identificación y el análisis de individuos VIH-1 positivos que controlan naturalmente la replicación viral, en ausencia de tratamiento antirretroviral, ha brindado pistas sobre los procesos celulares que pueden regular las proteínas y el ARN del virus, y que condicionan los procesos de replicación viral y de progresión clínica de la infección, así como la patología asociada. En la presente tesis doctoral, el principal objetivo de estudio se ha centrado en la proteína de unión al ADN de respuesta transactiva (TAR) 43 (“transactive response DNA-binding protein” (TARDBP o TDP-43)) la cual es reguladora importante del ARNm y, entre otros factores, de la enzima con actividad anti-VIH- 1, histona desacetilasa 6 (HDAC6). La sobreexpresión del constructo funcional parenteral de TDP-43 estabiliza los niveles de ARNm y de proteína de HDAC6, garantizando así sus funciones antivirales en células diana para la infección, afectando a la formación del poro de fusión e inhibiendo la infección por VIH-1, gracias a la actividad desacetiladora de microtúbulos (MT) de la enzima HDAC6, que actúa de forma independiente al tropismo del complejo de envoltura del virus. La regulación de la permisividad celular frente a la infección por VIH-1 por el eje TDP-43/HDAC6, se corrobora por silenciamiento específico del ARNm de TDP- 43, teniendo como consecuencia la disminución en los niveles tanto del ARNm como de la proteína de HDAC6, lo que genera un estatus celular de estabilización de MT que favorece la formación del poro de fusión y la infección del VIH-1, tras el contacto de la Env con el receptor CD4, debido a la reorganización de los MT y su modificación postraduccional por acetilación (por los niveles bajos de HDAC6). Además, y considerando que la Env del VIH-1 es un determinante citopático importante en la infección y replicación viral, y para determinar la funcionalidad viral de Env de virus primarios procedentes de pacientes VIH-1 positivos con fenotipos extremos, se caracterizaron varias Env provenientes de pacientes virémicos no progresores (VNP) o rápidos progresores (RP). Para ello, se realizó un análisis exhaustivo sobre distintos parámetros funcionales de la Env, observándose que los clones de Env, seleccionadas de ambos grupos de pacientes, mostraron capacidades similares de expresión, una afinidad similar por CD4, puesta de manifiesto en ensayos de transmisión de material viral célulacélula y de señalización por CD4 (medidos por acetilación de la subunidad atubulina de los MT), que rigen la capacidad de fusión de membrana (formación del poro de fusión) y de infección, siendo similares en estas Env funcionales. Además, las Env de los dos grupos inducen autofagia tardía por contacto con CD4 en células no infectadas, característica que correlaciona directamente con la actividad fusogénica de las Env. En el caso de los pacientes VNP, no se observa una relación entre la función autofágica tardía letal de las Env virales con la progresión de la enfermedad, si bien los clones de Env de individuos VNP son completamente funcionales y explicaría la viremia en estos pacientes. Todo apunta a que en pacientes VNP el estatus inmunitario aporta cierta estabilidad al fenotipo clínico no progresor. Como prueba de concepto, estas observaciones se confirmaron mediante el estudio de Env virales primarias de individuos infectados por VIH-1 con diferentes fenotipos clínicos, bajo las condiciones experimentales de sobreexpresión de TDP-43. Un aumento en el nivel de expresión de la proteína funcional de TDP-43 redujo fuertemente la actividad de infección de Env de individuos VNP y RP infectados por VIH-1 hasta los niveles de infección detectado para Env provenientes de pacientes controladores de élite, no progresores a largo plazo (LTNP-EC), cuya función viral es deficiente. Por el contrario, niveles bajos de TDP-43 endógeno, inducidos por silenciamiento específico mediante oligonucleótidos interferentes siRNA-TDP-43, favorecen significativamente la actividad de infección de Env primarias de VIH-1 de individuos VNP y RP. Sorprendentemente, el silenciamiento de TDP-43, que reduce los niveles de HDAC6 (su ARNm y proteína), generando un estado celular más permisivo a la infección, permite incluso la infección eficaz celular con pseudovirus portando Env primarias, deficientes en la función viral, de individuos LTNP-EC. Del mismo modo, se estudia cómo TDP-43 ejerce un efecto regulador sobre HDAC6 en células productoras de viriones, al garantizar, mediante la estabilización en los niveles de ARN mensajero (ARNm) y proteína, las funciones autofágicas degradativas de la enzima desacetilasa. Debido a ello, los niveles de proteínas virales Pr55Gag y Vif se ven reducidos, afectando así a la replicación, producción de viriones e infectividad de los mismos. Tras el silenciamiento de TDP-43, se comprueba cómo la actividad autofágica dependiente de HDAC6 se ve reducida, aumentando así la producción viral y la infectividad de los virus generados bajo estas condiciones experimentales, evidenciando la capacidad reguladora de TDP-43 sobre HDAC6 y, consecuentemente, sus actividades antivirales.HIV/AIDS remains a global threat despite the remarkable efforts made by the scientific and health communities to understand this viral infection, to design new drugs or improve existing ones, as well as develop advanced therapies and design vaccines for functional cure, prevention and viral eradication. The identification and analysis of HIV-1 positive individuals who naturally control viral replication in the absence of antiretroviral treatment has provided clues about the cellular processes that might interact with viral proteins and RNA, and define subsequent viral replication and clinical progression. Thus, in this doctoral thesis, the object of study has been focused on the transactive response (TAR) DNA-binding protein (TARDBP or TDP-43), which is an important regulator of mRNA and is known to stabilize the anti-HIV-1 factor, histone deacetylase 6 (HDAC6). The overexpression of the TDP-43 wild type construct stabilizes HDAC6 mRNA and protein levels, thus guaranteeing its antiviral functions in permissive cells for infection, impairing the formation of the fusion pore due to the deacetylating activity in microtubules (MTs) of HDAC6 and independently of the tropism of the viral envelope complex of the virus and, therefore, decreasing the infection ability of the virus. The regulation of cell permissiveness against HIV-1 infection by the TDP-43/HDAC6 axis is corroborated by specific silencing of TDP-43 mRNA, resulting in a decrease in both mRNA and protein levels. of HDAC6, which generates a cellular status of MT stabilization that favors the formation of the fusion pore and the infection of HIV-1, after contact of Env with the CD4 receptor, due to the reorganization of the MTs and their modification post-translational by acetylation (because of low levels of HDAC6). In addition, and considering that the Env of HIV-1 is an important cytopathic determinant in viral infection and replication, and to determine the viral functionality of Env from primary viruses with extreme phenotypes, several Env from viremic non-progressors patients (VNP) or rapid progressors (RP) were characterized. For this, an exhaustive analysis was carried out on different functional parameters of the Env, observing that the Env clones, selected from both groups of patients, showed similar expression capacities, a similar affinity for CD4, revealed in transmission tests of cell-cell viral material and CD4 signaling (measured by acetylation of the a-tubulin subunit of MT), which govern the capacity for membrane fusion (formation of the fusion pore) and infection, being similar in these functional Env . In addition, the Env of the two groups induce late autophagy by contact with CD4 in uninfected cells, a characteristic that directly correlates with the fusogenic activity of the Env. In the case of VNP patients, no relationship is observed between the lethal late autophagic function of viral Env with disease progression, although the Env clones of VNP individuals are fully functional and would explain the viremia in these patients. All these data points to the fact that in VNP patients the immune status provides a certain stability to the non-progressor clinical phenotype. As a proof of concept, these observations were confirmed by studying primary viral Env from HIV-1 infected individuals with different clinical phenotypes, under the experimental conditions of TDP-43 overexpression. An increase in the expression level of wt-TDP-43 strongly reduced Env infection activity from HIV-1 infected VNP and RP individuals to the infection levels detected for Env from elite controllers long-term non-progressors patients (LTNP-EC), whose viral function is impaired. In contrast, low levels of endogenous TDP-43, induced by specific silencing with interfering oligos siRNA-TDP-43, significantly favor the infection activity of primary HIV-1 Env from VNP and RP individuals. Surprisingly, the silencing of TDP-43, which reduces the levels of HDAC6 (its mRNA and protein), generating a cellular state more permissive to infection, even allows efficient cellular infection with pseudoviruses carrying primary Env, deficient in viral function, of LTNP-EC individuals. In the same way, it is also verified how TDP-43 exerts a regulatory effect on HDAC6 in virion-producing cells, by guaranteeing, by stabilizing the levels of mRNA and protein, the autophagic degrading functions of the deacetylating enzyme. Due to this, the levels of viral proteins Pr55Gag and Vif are reduced, thus affecting their replication, virion production and infectivity. After the silencing of TDP-43, it is verified how the autophagic activity dependent on HDAC6 is reduced, thus increasing the viral production and the infectivity of the viruses generated under these experimental conditions, evidencing the regulatory capacity of TDP- 43 on HDAC6 and, consequently, its antiviral activities