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

Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR - J. Exp. Med. (1997)

Bottom Line: We found that isolates of HIV-1 from early in the course of infection predominantly used CCR5 for infection.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.

View Article: PubMed Central - PubMed

Affiliation: Aaron Diamond AIDS Research Center, The Rockefeller University, New York 10016, USA.

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.

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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-1JRFL, HIV-1HXB2) or from primary virus env clones.  Three of the primary env clones came from a patient with rapid disease  progression (9–12, 13–14, 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).
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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-1JRFL, HIV-1HXB2) or from primary virus env clones. Three of the primary env clones came from a patient with rapid disease progression (9–12, 13–14, 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).

Mentions: To test this hypothesis, we generated full-length env clones by direct DNA PCR amplification from sequential PBMC samples from patient B (33). Env clones 9-12 and 13-14 were derived from early NSI viruses (Table 1; 5/85 and 11/86, respectively), whereas env clone 15-1 was derived from an SI isolate (Table 1; 6/88). HIV-1 virions containing a luciferase reporter gene were pseudotyped with the cloned envelope glycoproteins and used in single cycle infectivity assays to evaluate viral entry into CD4+ cells expressing each of the β-chemokine receptors or CXCR-4. As shown in Fig. 2, luciferase activity was detected in cells expressing CCR5, CCR3, and CCR2b after infection with control viruses pseudotyped with envelope glycoproteins from a macrophage-tropic, NSI strain of HIV-1 (HIV-1JRFL) (Fig. 2 A). In contrast, a TCLA, SI virus (HIV-1HXB2) was only able to infect cells expressing CXCR-4. Virions pseudotyped with envelope glycoproteins from two of the primary env clones from patient B (9–12, 13–14) infected cells expressing CCR5, and to a lesser extent, CCR2b and CCR3, while a third clone (15-1) only infected cells expressing CXCR-4. Another primary HIV-1 env clone derived from a long-term survivor (DH) used CCR5 and CCR3 for infection. Sequencing of the V3 loop of env clones 9-12, 13-14, and DH revealed the presence of uncharged amino acids at positions 11 and 28 (Fig. 2 B), characteristic of NSI viruses, while clone 15-1 had a positively charged residue at position 11, characteristic of SI viruses (35, 36).


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

Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR - J. Exp. Med. (1997)

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-1JRFL, HIV-1HXB2) or from primary virus env clones.  Three of the primary env clones came from a patient with rapid disease  progression (9–12, 13–14, 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).
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Related In: Results  -  Collection

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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-1JRFL, HIV-1HXB2) or from primary virus env clones. Three of the primary env clones came from a patient with rapid disease progression (9–12, 13–14, 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).
Mentions: To test this hypothesis, we generated full-length env clones by direct DNA PCR amplification from sequential PBMC samples from patient B (33). Env clones 9-12 and 13-14 were derived from early NSI viruses (Table 1; 5/85 and 11/86, respectively), whereas env clone 15-1 was derived from an SI isolate (Table 1; 6/88). HIV-1 virions containing a luciferase reporter gene were pseudotyped with the cloned envelope glycoproteins and used in single cycle infectivity assays to evaluate viral entry into CD4+ cells expressing each of the β-chemokine receptors or CXCR-4. As shown in Fig. 2, luciferase activity was detected in cells expressing CCR5, CCR3, and CCR2b after infection with control viruses pseudotyped with envelope glycoproteins from a macrophage-tropic, NSI strain of HIV-1 (HIV-1JRFL) (Fig. 2 A). In contrast, a TCLA, SI virus (HIV-1HXB2) was only able to infect cells expressing CXCR-4. Virions pseudotyped with envelope glycoproteins from two of the primary env clones from patient B (9–12, 13–14) infected cells expressing CCR5, and to a lesser extent, CCR2b and CCR3, while a third clone (15-1) only infected cells expressing CXCR-4. Another primary HIV-1 env clone derived from a long-term survivor (DH) used CCR5 and CCR3 for infection. Sequencing of the V3 loop of env clones 9-12, 13-14, and DH revealed the presence of uncharged amino acids at positions 11 and 28 (Fig. 2 B), characteristic of NSI viruses, while clone 15-1 had a positively charged residue at position 11, characteristic of SI viruses (35, 36).

Bottom Line: We found that isolates of HIV-1 from early in the course of infection predominantly used CCR5 for infection.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.

View Article: PubMed Central - PubMed

Affiliation: Aaron Diamond AIDS Research Center, The Rockefeller University, New York 10016, USA.

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.

Show MeSH
Related in: MedlinePlus