Change in coreceptor use correlates with disease progression in HIV-1--infected individuals

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, syncytium-inducing (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.

Figure 1

Inhibition of sequential HIV-1 isolates by β-chemokines. Biologically cloned isolates of HIV-1 were used to infect PHA-activated normal donor PBMCs in the presence of increasing concentrations of RANTES (▪), MIP-1α (•), MIP-1β (▴), or all three combined (♦). HIV-1 p24 antigen was measured in culture supernatants on day 7 after virus inoculation. The percent inhibition was calculated based on control cultures infected without added chemokines.

Figure 2

Coreceptor use by primary HIV-1 env-pseudotyped virions. (A) HOS.CD4 expressing either CCR1, CCR2, CCR3, CCR4, CCR5, or CXCR-4 were infected with HIV-1 virions carrying a luciferase reporter gene and pseudotyped with envelope glycoproteins from either control viruses (HIV-1_JRFL, HIV-1_HXB2) or from primary virus env clones. Three of the primary env clones came from a patient with rapid disease progression (–, –, 15-1), while the fourth clone was from a patient with long-term asymptomatic infection (DH). Luciferase activity was calculated by subtracting the background measurements made using env(−) virions and HOS.CD4 cells expressing only the retroviral vector, pBABE. (B) Deduced amino acid sequences of the V3 domain of gp120 from cloned primary HIV-1 env genes. Bold type indicates amino acids at positions 11 and 28 which are associated with the SI phenotype of the virus (35, 36).

Figure 2

Coreceptor use by primary HIV-1 env-pseudotyped virions. (A) HOS.CD4 expressing either CCR1, CCR2, CCR3, CCR4, CCR5, or CXCR-4 were infected with HIV-1 virions carrying a luciferase reporter gene and pseudotyped with envelope glycoproteins from either control viruses (HIV-1_JRFL, HIV-1_HXB2) or from primary virus env clones. Three of the primary env clones came from a patient with rapid disease progression (–, –, 15-1), while the fourth clone was from a patient with long-term asymptomatic infection (DH). Luciferase activity was calculated by subtracting the background measurements made using env(−) virions and HOS.CD4 cells expressing only the retroviral vector, pBABE. (B) Deduced amino acid sequences of the V3 domain of gp120 from cloned primary HIV-1 env genes. Bold type indicates amino acids at positions 11 and 28 which are associated with the SI phenotype of the virus (35, 36).