Change in Coreceptor Use Correlates with Disease Progression in HIV-1–Infected Individuals

TLDR

Human Immunodeficiency Virus type 1 requires coreceptors such as CCR5 and CXCR4 to fuse with CD4+ cells, with CCR5 used by nonsyncytium‑inducing strains and CXCR4 by syncytium‑inducing strains. The study investigated whether sequential HIV‑1 isolates from patients show changes in coreceptor usage over time and whether such changes correlate with disease progression. Early isolates predominantly used CCR5, but in progressing patients the virus expanded to CCR5, CCR3, CCR2b, and CXCR4, with CXCR4 use linked to a switch from nonsyncytium to syncytium‑inducing phenotype, loss of chemokine sensitivity, and declining CD4 counts, indicating that coreceptor expansion associates with AIDS progression.

Abstract

Recent studies have identified several coreceptors that are required for fusion and entry of Human Immunodeficiency Virus type 1 (HIV-1) into CD4+ cells. One of these receptors, CCR5, serves as a coreceptor for nonsyncytium inducing (NSI), macrophage-tropic strains of HIV-1, while another, fusin or CXCR-4, functions as a coreceptor for T cell line–adapted, syncytiuminducing (SI) strains. Using sequential primary isolates of HIV-1, we examined whether viruses using these coreceptors emerge in vivo and whether changes in coreceptor use are associated with disease progression. We found that isolates of HIV-1 from early in the course of infection predominantly used CCR5 for infection. However, in patients with disease progression, the virus expanded its coreceptor use to include CCR5, CCR3, CCR2b, and CXCR-4. Use of CXCR-4 as a coreceptor was only seen with primary viruses having an SI phenotype and was restricted by the env gene of the virus. The emergence of variants using this coreceptor was associated with a switch from NSI to SI phenotype, loss of sensitivity to chemokines, and decreasing CD4+ T cell counts. These results suggest that HIV-1 evolves during the course of infection to use an expanded range of coreceptors for infection, and that this adaptation is associated with progression to AIDS.