Viral Characteristics Associated with the Clinical Nonprogressor Phenotype Are Inherited by Viruses from a Cluster of HIV-1 Elite Controllers

A small group of HIV-1-infected individuals, called long-term nonprogressors (LTNPs), and in particular a subgroup of LTNPs, elite controllers (LTNP-ECs), display permanent control of viral replication and lack of clinical progression. This control is the result of a complex interaction of host, immune, and viral factors. We identified, by phylogenetic analysis, a cluster of LTNP-ECs infected with very similar low-replication HIV-1 viruses, suggesting the contribution of common viral features to the clinical LTNP-EC phenotype. HIV-1 envelope (Env) glycoprotein mediates signaling and promotes HIV-1 fusion, entry, and infection, being a key factor of viral fitness in vitro, cytopathicity, and infection progression in vivo Therefore, we isolated full-length env genes from viruses of these patients and from chronically infected control individuals. Functional characterization of the initial events of the viral infection showed that Envs from the LTNP-ECs were ineffective in the binding to CD4 and in the key triggering of actin/tubulin-cytoskeleton modifications compared to Envs from chronic patients. The viral properties of the cluster viruses result in a defective viral fusion, entry, and infection, and these properties were inherited by every virus of the cluster. Therefore, inefficient HIV-1 Env functions and signaling defects may contribute to the low viral replication capacity and transmissibility of the cluster viruses, suggesting a direct role in the LTNP-EC phenotype of these individuals. These results highlight the important role of viral characteristics in the LTNP-EC clinical phenotype. These Env viral properties were common to all the cluster viruses and thus support the heritability of the viral characteristics.IMPORTANCE HIV-1 long-term nonprogressor elite controller patients, due to their permanent control of viral replication, have been the object of numerous studies to identify the factors responsible for this clinical phenotype. In this work, we analyzed the viral characteristics of the envelopes of viruses from a phylogenetic cluster of LTNP-EC patients. These envelopes showed ineffective binding to CD4 and the subsequent signaling activity to modify actin/tubulin cytoskeletons, which result in low fusion and deficient entry and infection capacities. These Env viral characteristics could explain the nonprogressor clinical phenotype of these patients. In addition, these inefficient env viral properties were present in all viruses of the cluster, supporting the heritability of the viral phenotype.A.V.-F.’s lab is supported by the European regional development fund (ERDF), SAF2015-64118-R (Ministerio de Economia y Competitividad, MINECO, Spain) Fundación CajaCanarias BIO29, UNLL10-3E-783 (ERDF and Fundación CajaCanarias), and by the Spanish AIDS Research Network RIS-RETIC grants RD16/0025/0011 and RD12/0017/0034 and cofunded by ISCIII and ERDF (RIS-RETIC) grants. R.C.-R., M.-S.V., L.A.-R., S.M.-H., and D.M.-A. are funded by RD16/0025/0011, RD12/0017/0034-(RIS-RETIC), SAF2011-24671-FPI, TESIS2015-010038- and TESIS2017010116-Programa Predoctoral de Formación del Personal Investigador, Agencia Canaria de Investigación, Innovación y Sociedad de la Información de la Consejería de Economía, Industria, Comercio y Conocimiento y por el Fondo Social Europeo (FSE) Programa Operativo Integrado de Canarias 2014-2020, Eje 3 Tema Prioritario 74 (85%), and European Social Fund and Fundación CajaCanarias BIO29-fellowships. Work in J.B.’s lab is supported by grants PI14/01307 and PI17/01518 from the Fondo de Investigaciones Sanitarias (FIS, Instituto de Salud Carlos III, ISCIII) and RIS-RETIC grants RD12/0017/0002 and RD16/0025/0041, cofunded by ISCIII and FEDER (EU). 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 Catalan Government (Generalitat de Catalunya). IrsiCaixa and IGTP are part of CERCA Programme/Generalitat de Catalunya. Work in C.L.-G.’s lab was supported by grants SAF (2010-17226) and (2016-77894-R) from MINECO (Spain) and FIS (PI 13/02269, ISCIII) and in part by the RIS-RETIC grants RD06/006/0036 and RD12/0017/0028 funded by the ISC III-FEDER. M.P. has support from RIS-RETIC contract RD12/0017/0036. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Work in P.L.’s lab is supported by Bijzonder Onderzoeksfonds KU Leuven (BOF)' no. OT/14/115 and the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO) (G066215N).S