HIV-1 envelope glycoproteins isolated from Viremic Non-Progressor individuals are fully functional and cytopathic

Romina Cabrera-Rodríguez,María Pernas,Martine Biard-Piechaczyk,Sara Marrero-Hernández,Daniel Márquez-Arce,Silvia Marfil,Agustín Valenzuela-Fernández,Silvia Pérez-Yanes,Judith Estévez-Herrera,Isabel Olivares,Cecilio López-Galíndez,Bonaventura Clotet,Julià Blanco,Veronique Hebmann,Lucile Espert,Victor Urrea,Concepción Casado,Cecilia Cabrera

doi:10.1038/s41598-019-42075-3

Abstract

In untreated HIV-1-infected individuals, viremia is positively associated with disease progression. However, some viremic non progressors (VNPs) individuals show paradoxical high CD4+ T cell counts. HIV-1 envelope glycoprotein complex (Env) is a major cytopathic determinant in viral replication; therefore, we have deeply characterized Env function in this rare clinical phenotype. Full-length Env clones isolated from individuals with Viral Load (VL) > 10,000 copies/mL classified as VNPs (n = 15) or rapid progressors (RPs, n = 17) were geno- and phenotypically analyzed by determining diversity, expression, CD4 binding/signaling, fusogenicity, infectivity and autophagy induction. Selected Env clones from VNPs and RPs (n = 32) showed similar expression, fusion and infection abilities. Env clones from both groups showed similar affinity for CD4 during cell-to-cell transmission and consistently induced similar levels of CD4 signaling, measured by α-tubulin acetylation. Moreover, we demonstrate for the first time that primary Env clones from VNP and RP induce autophagy in uninfected cells and that this feature correlated with fusogenic capacity but was unrelated to disease progression. In conclusion, our data suggest that Env clones from VNP individuals are fully functional. Therefore, the paradoxical CD4+ T cell count stability coexisting with high levels of viral replication is unrelated to Env function.

Highlights

Human immunodeficiency virus type 1 (HIV-1) infection destroys CD4+ T cells and compromises the function of the immune system leading to acquired immunodeficiency syndrome (AIDS)[1,2]
Understanding viral factors associated with the viremic non-progressors (VNPs) phenotype in HIV-1 infection may help to unveil cytopathic mechanisms of CD4+ T cell depletion in vivo
Env is a key determinant of HIV-1 cytopathicity and its fusogenic activity has been shown to be a key determinant in CD4+ T cell loss, both in vitro and in vivo[16,27,28]

Summary

Introduction

Human immunodeficiency virus type 1 (HIV-1) infection destroys CD4+ T cells and compromises the function of the immune system leading to acquired immunodeficiency syndrome (AIDS)[1,2]. High levels of viral replication, either as a consequence of poor or inefficient immunological responses or particular viral cytopathic factors, are associated with rapid progression to AIDS6–8 Besides these well-characterized clinical phenotypes, in an extremely low percentage of patients, known as viremic non-progressors (VNPs), a high level of viral replication is accompanied by a paradoxical slow CD4+ T-cell destruction[9]. Assuming the widely described major role of Env in viral fitness and pathogenesis[5,16,17,18], we hypothesized that Env isolated from VNPs might have specific features leading to the VNP clinical outcome To test this hypothesis, we have deeply characterized full-length Env clones isolated from VNPs by evaluating their genotypical and phenotypical features (CD4 binding, signaling capacity and autophagy induction). Our data show that VNPs harbor fully signaling-and fusion-competent Envs, which show fully cytopathic potential as assessed by their ability to induce autophagy in bystander uninfected CD4+ T cells

Methods

Results

Conclusion