Coevolution of RANTES Sensitivity and Mode of CCR5 Receptor Use by Human Immunodeficiency Virus Type 1 of the R5 Phenotype

Abstract

The evolution of human immunodeficiency virus type 1 (HIV-1) coreceptor use has been described as the acquisition of CXCR4 use linked to accelerated disease progression. However, CXCR4-using virus can be isolated only from approximately one-half of individuals with progressive HIV-1 disease. The other half continue to yield only CCR5-using viruses (R5 phenotype) throughout the course of disease. In the present work, the use of receptor chimeras between CCR5 and CXCR4 allowed us to study the evolution of HIV-1 with the R5 phenotype, which was not revealed by studies of wild-type coreceptor use. All together, 246 isolates (173 with the R5 phenotype) from 31 individuals were tested for their ability to infect cells through receptor chimeras. R5 narrow virus was able to use only wild-type CCR5, whereas R5 broad(1) to R5 broad(3) viruses were able to use one to three chimeric receptors, respectively. Broad use of chimeric receptors was interpreted as an increased flexibility in the mode of receptor use. R5 broad isolates showed higher infectivity in cells expressing wild-type CCR5 than R5 narrow isolates. Also, the increased flexibility of R5 broad isolates was concomitant with a lower sensitivity to inhibition by the CC chemokine RANTES. Our results indicate a close relationship between HIV-1 phenotypic changes and the pathogenic process, since the mode and efficiency of CCR5 use as well as the decrease in the RANTES sensitivities of isolated viruses are significantly correlated with CD4؉ -T-cell decline in a patient. One possible explanation is that ligand competition at the CCR5 receptor or changed CCR5 availability may shape the outcome of HIV-1 infection.

Transmitted/Founder and Chronic HIV-1 Envelope Proteins Are Distinguished by Differential Utilization of CCR5

“…The more promiscuous utilization of CCR5 conformations by CC Envs may reflect selection pressures in chronic infection where neutralizing antibodies are abundant and certain populations of CD4 ϩ CCR5 ϩ cells have been diminished or otherwise altered by viral cytopathicity. Earlier studies have shown that R5 viruses can become increasingly resistant to entry inhibitors over time, consistent with alterations in CCR5 use (73)(74)(75). More promiscuous utilization of CCR5 could expand viral tropism under these conditions, in contrast to de novo infection of naïve hosts where virus infection of a more homogeneous population of CD4 ϩ CCR5 ϩ cells could be favored.…”

Human Immunodeficiency Virus Type 1 V1-to-V5 Envelope Variants from the Chronic Phase of Infection Use CCR5 and Fuse More Efficiently than Those from Early after Infection

“…Thus, in vivo, the CCR5 receptor may have different conformations in the presence of chemokines. It has been shown that envelopes from the late phase of infection compared to the variants from the chronic stage of disease display an increased ability to bind a broad range of chimeric CCR5 receptors (30). Therefore, an ability to bind different structural forms of the CCR5 receptor may explain the increased CCR5 usage among chronic-stage variants compared to the earlyinfection isolates.…”

HIV Type 1 from a Patient with Baseline Resistance to CCR5 Antagonists Uses Drug-Bound Receptor for Entry

“…Patients with more advanced disease have a greater likelihood of harboring X4-utilizing viruses [52][53][54] and have R5-tropic viruses with reduced sensitivity to RANTES and the CCR5 antagonists TAK779 and AD101 compared with patients at earlier disease stages. [55][56][57][58] As a consequence, these patients may fail R5 antagonist therapy via either outgrowth of minor preexisting X4-utilizing populations or the continued use of CCR5 in the presence of drug. In patients treated earlier during the course of infection, who have lower levels of circulating X4-tropic viral isolates, continued use of R5 may be a more common resistance pathway.…”