HIV-1 dynamics and coreceptor usage in Maraviroc-treated patients with ongoing replication

Abstract

There is evidence that HIV-1 evolution under maraviroc (MVC) pressure can lead to the selection of either X4-tropic variants and/or R5-tropic, MVC-resistant isolates. However, the viral dynamics of HIV-1 variants in patients with virological failure (VF) on MVC-containing regimens remain poorly studied. Here, we investigated the V3 loop evolution of HIV-1 on MVC in relation to coreceptor usage and the nature of HIV-1 quasispecies before MVC therapy using bulk population sequences and ultradeep sequencing. The majority of patients had no detectable minority X4 variant at baseline. The evolution of tropism was followed up until VF and showed three possibilities for viral evolution in these patients: emergence of preexisting X4 variants, de novo selection of R5 variants presenting V3 loop mutations, or replication of R5 variants without selection of known mutations.

Fig 1

V3 quasispecies at baseline and at failure. Phylogenetic analysis, based on the neighbor-joining method, of the HIV-1 V3 region using 454 sequences at M0 and population sequences at times indicated for 4 patients. Corresponding tropisms are indicated between brackets. Only consensus sequences are represented for patient 6.

Fig 2

Virological evolution of the V3 region in the patients failing on MVC. The number of 454 sequences used for the analysis is determined in the first column. Prox M indicated the 454 sequence found to be the most closely related to the bulk population sequence at the studied time. For patient 10, no proximal sequence was identified to M6 bulk sequence. No 454 data were available for patients 7 and 14. Columns for amino acids at positions 11 and 25 are in gray. Black arrows indicate positions of known mutations. Black circles indicate positions of mutations observed in this study.