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

Romina Cabrera-Rodríguez (1) , Veronique Hebmann (2) , Silvia Marfil (3) , María Pernas (4) , Sara Marrero-Hernández (1) , Cecilia Cabrera (3) , Victor Urrea (3) , Concepción Casado (4) , Isabel Olivares (4) , Daniel Márquez-Arce (1) , Silvia Pérez-Yanes (1) , Judith Estévez-Herrera (1) , Bonaventura Clotet (3) , Lucile Espert (2) , Cecilio López-Galíndez (4) , Martine Biard-Piechaczyk (2) , Agustín Valenzuela-Fernández (1) , Julià Blanco (3, 5)

1 ULL - Universidad de La Laguna [Tenerife - SP]
2 IRIM - Institut de Recherche en Infectiologie de Montpellier
3 IrsiCaixa (Institut de Recerca de la Sida)
4 CNM - Centro Nacional de Microbiología [ISCIII, Madrid, Spain]
5 Universitat de Vic

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. 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. However, the rate of CD4 + T-cell depletion and the time to onset of AIDS symptoms are highly variable among HIV-1 infected individuals 3. This variability defines several clinically relevant groups of HIV-1 infected individuals, such as long-term non progressors (LTNPs) that show, in general, a low viremia level (below standard detection limits in some cases) and a slow progression to AIDS 3. The reduced level of viral replication has been associated to the magnitude and quality of the immune responses, in particular CD8-mediated control, which results in low or even suppressed viral replication 4. Virological factors that impair the in vivo viral fitness have also been shown to contribute to this phenotype 5. In an opposed setting, 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 AIDS 6-8 .

Domaines: Sciences du Vivant [q-bio]; Microbiologie et Parasitologie; Virologie

Romina Cabrera-Rodríguez, Veronique Hebmann, Silvia Marfil, María Pernas, Sara Marrero-Hernández, et al.. HIV-1 envelope glycoproteins isolated from viremic non-progressor individuals are fully functional and cytopathic. Scientific Reports, 2019, 9, pp.5544. ⟨10.1038/s41598-019-42075-3⟩. ⟨hal-02337648⟩