The density of coreceptors at the surface of CD4+ T cells contributes to the extent of human immunodeficiency virus type 1 viral replication-mediated T cell death.
Chemokine receptors serve as coreceptors for HIV-1 entry into CD4(+) T cells. Several reports have mentioned that density of CCR5 expression modulates in vitro viral replication and in vivo the course of the disease. Our goal was to investigate the impact of coreceptor density at the surface of a CD4(+) cell line on HIV-1 entry, replication, spreading, and programmed cell death. We engineered a CEM cell line that expresses constitutively CD4 and CXCR4 and CCR5 after transfection. This model allows us to compare the effect of the X4 and R5 strains to induce T cell death in the same T cell host. We show here that the extent of T cell death correlates with the rate of virus replication. X4 induces faster T cell death than R5 that depends at least in part on the higher density of CXCR4 compared to CCR5. Furthermore, sorting CEM populations expressing low, intermediate, and high densities of CCR5 molecules but constant amount of CD4, we found that the capacity to induce T cell death depends at least in part on the level of CCR5 when low amount of virus was used to infect the CEM cells. Moreover, viral transcription, assessed by cell-associated HIV-1 RNA/DNA ratio, was increased in CCR5high as compared to CCR5low cells, while inhibition of replication by zidovudine was more effective in CCR5low cells. Our data indicate that the density of chemokine receptors expressed on CD4(+) T cells may be a critical parameters for the cytopathic effect of HIV strains and may have major impact on CD4 T cell depletion during HAART.
Lelièvre
Jean-Daniel
JD
INSERM U421, Faculté de Médecine Henri Mondor, Créteil, France.
Petit
Frédéric
F
Perrin
Luc
L
Mammano
Fabrizio
F
Arnoult
Damien
D
Ameisen
Jean-Claude
JC
Corbeil
Jacques
J
Gervaix
Alain
A
Estaquier
Jérome
J
D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000502:physiology / Q000821:virology*; D016923:Cell Death; D002460:Cell Line; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D014779:Virus Replication
D019713:Receptors, CCR5; D019718:Receptors, CXCR4