Shift of clinical human immunodeficiency virus type 1 isolates from X4 to R5 and prevention of emergence of the syncytium-inducing phenotype by blockade of CXCR4.
The emergence of X4 human immunodeficiency virus type 1 (HIV-1) strains in HIV-1-infected individuals has been associated with CD4(+) T-cell depletion, HIV-mediated CD8(+) cell apoptosis, and an impaired humoral response. The bicyclam AMD3100, a selective antagonist of CXCR4, selected for the outgrowth of R5 virus after cultivation of mixtures of the laboratory-adapted R5 (BaL) and X4 (NL4-3) HIV strains in the presence of the compound. The addition of AMD3100 to peripheral blood mononuclear cells infected with X4 or R5X4 clinical HIV isolates displaying the syncytium-inducing phenotype resulted in a complete suppression of X4 variants and a concomitant genotypic change in the V2 and V3 loops of the envelope gp120 glycoprotein. The recovered viruses corresponded genotypically and phenotypically to R5 variants in that they could no longer use CXCR4 as coreceptor or induce syncytium formation in MT-2 cells. Furthermore, the phenotype and genotype of a cloned R5 HIV-1 virus converted to those of the R5X4 virus after prolonged culture in lymphoid cells. However, these changes did not occur when the infected cells were cultured in the presence of AMD3100, despite low levels of virus replication. Our findings indicate that selective blockade of the CXCR4 receptor prevents the switch from the less pathogenic R5 HIV to the more pathogenic X4 HIV strains, a process that heralds the onset of AIDS. In this article, we show that it could be possible to redirect the evolution of HIV so as to impede the emergence of X4 strains or to change the phenotype of already-existing X4 isolates to R5.
Esté
J A
JA
Institut de Recerca de la SIDA-Caixa, Retrovirology Laboratory, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain. jaeste@ns.hugtip.scs.es
Cabrera
C
C
Blanco
J
J
Gutierrez
A
A
Bridger
G
G
Henson
G
G
Clotet
B
B
Schols
D
D
De Clercq
E
E
D000220:Adaptation, Biological; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001596:Benzylamines; D000080027:Cyclams; D005838:Genotype; D015726:Giant Cells / Q000821:virology; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics; D010641:Phenotype; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D014779:Virus Replication
D019380:Anti-HIV Agents; D001596:Benzylamines; D000080027:Cyclams; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D006571:Heterocyclic Compounds; D010446:Peptide Fragments; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C088327:plerixafor