The HR2 polymorphism N140I in the HIV-1 gp41 combined with the HR1 V38A mutation is associated with a less cytopathic phenotype

Open Access

Abstract

Altres ajuts: This work was supported by the FIS project 07/0418 (to CC), the Spanish AIDS network, "RIS, Red Temática Cooperativa de Investigación en SIDA (RD06/0006)" and the CHAIN European Consortium. C. Cabrera and J. Blanco are researchers 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). F. Cunyat is supported by the FIS project 07/0418 and VS is supported by grants from CHAIN, Collaborative HIV and Anti-HIV Drug-Resistance Network, Integrated Project no.223131, funded by the European-Commission Framework-7 Program. MC is supported by a RIS contract. This work is part of the PhD thesis of F. Cunyat at Universitat Autònoma de Barcelona, Barcelona, Spain. ; Resistance to the fusion inhibitor enfuvirtide (ENF) is achieved by changes in the gp41 subunit of the HIV envelope glycoprotein (Env). Specific ENF-associated mutational pathways correlate with immunological recovery, even after virological failure, suggesting that the acquisition of ENF resistance alters gp41 pathogenicity. To test this hypothesis, we have characterized the expression, fusion capability, induction of CD4 + T cell loss and single CD4 + T cell death of 48 gp41 proteins derived from three patients displaying different amino acids (N, T or I) at position 140 that developed a V38A mutation after ENF-based treatment. In all cases, intra-patient comparison of Env isolated pre- or post-treatment showed comparable values of expression and fusogenic capacity. Furthermore, Env with either N or T at position 140 induced comparable losses of CD4 + T-cells, irrespective of the residue present at position 38. Conversely, Env acquiring the V38A mutation in a 140I background induced a significantly reduced loss of CD4 + T cells and lower single-cell death than did their baseline controls. No altered ability to induce single-cell death was observed in the other clones. Overall, primary gp41 proteins with both V38A and N140I changes ...