Inhibition of R5X4 dualtropic HIV-1 primary isolates by single chemokine co-receptor ligands.
The susceptibility of HIV-1 to chemokine-mediated inhibition may be lost as a consequence of the expanded usage of chemokine co-receptors frequently occurring in clade B isolates obtained from individuals with advanced disease. Since chemokine-based immune intervention is under intense investigation, it is crucial to determine its potential effect on primary dualtropic HIV isolates characterized by simultaneous utilization of CCR5 and CXCR4 chemokine co-receptors (R5X4 viruses). In the present study, the CCR5 binding chemokine regulated upon activation normal T cell expressed and secreted (RANTES) strongly inhibited the replication of two of eight primary R5X4 viruses in mitogen-activated primary peripheral blood mononuclear cells (PBMC). The CXCR4 antagonist AMD3100 efficiently suppressed the replication of other two HIV isolates, whereas the remaining four viruses were partially inhibited by treatment with either RANTES or AMD3100. The potency of chemokine-mediated inhibition was influenced by PBMC donor variability, but it was usually independent from the levels of expression of CCR5 or CXCR4. Dual co-receptor usage was maintained by the viruses after two serial passages on U87.CD4 astrocytic cell lines expressing exclusively either CCR5 or CXCR4. The gp120 env variable domains were sequenced before and after passages on U87.CD4 cells. Virus replication into U87.CD4-CXCR4 cells did not result in changes in the V3 region but perturbed the dominant env V4 sequence. Interestingly, double passage onto U87.CD4-CXCR4 cells determined the loss of susceptibility to RANTES inhibition. In conclusion, interference with CCR5 may efficiently inhibit the replication of at least some dualtropic HIV-1 strains, whereas forced CXCR4 usage may result in viral escape from CCR5-dependent inhibitory effects.
Ghezzi
S
S
AIDS Immunopathogenesis Unit, DIBIT, San Raffaele Scientific Institute, Milan, Italy.
Menzo
S
S
Brambilla
A
A
Bordignon
P P
PP
Lorini
A L
AL
Clementi
M
M
Poli
G
G
Vicenzi
E
E
D000595:Amino Acid Sequence; D001483:Base Sequence; D001596:Benzylamines; D065100:CCR5 Receptor Antagonists; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism / Q000494:pharmacology; D000080027:Cyclams; D004279:DNA, Viral; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000821:virology; D008024:Ligands; D008969:Molecular Sequence Data; D019713:Receptors, CCR5 / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects
D001596:Benzylamines; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D000080027:Cyclams; D004279:DNA, Viral; D015699:HIV Envelope Protein gp120; D006571:Heterocyclic Compounds; D008024:Ligands; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C088327:plerixafor