CCR5 density levels on primary CD4 T cells impact the replication and Enfuvirtide susceptibility of R5 HIV-1.
OBJECTIVE
Studies in cell lines have demonstrated that CCR5 coreceptor levels influence the replication efficiency and Enfuvirtide (T-20) susceptibility of R5 HIV-1 strains. At present, however, the role that CCR5 levels on primary CD4 T cells--which are markedly lower than in cell lines and vary only approximately fivefold among most donors--may play in virus replication levels or susceptibility to T-20 is not known. In the present study we evaluated the impact of differences in CCR5 levels among donor CD4 T cells on the infection efficiency and T-20 susceptibility of R5 HIV-1.


METHODS
CD4 and CCR5 density levels were determined by Quantitative FACS analysis. Virus infectivity assays were conducted in cell lines and primary cells. Associations between coreceptor density, virus replication and T-20 sensitivity were tested using the Spearman's correlation test.


RESULTS
We found a positive correlation (r, 0.55; P = 0.011) between CCR5 density levels on primary CD4 T cells and replication of R5 HIV-1. In cell lines expressing physiologically relevant levels of CD4 and CCR5, T-20 was significantly more potent in cells with low CCR5 levels. In addition, T20 50% inhibitory concentrations for R5 HIV-1 replication varied approximately 100-fold among primary cells from different donors and they were positively correlated with CCR5 density values (r, 0.84; P = 0.00004).


CONCLUSIONS
These results suggest that CCR5 density levels in HIV-1 patients may impact the activity of T-20 against R5 strains and that therapeutic approaches to alter CCR5 density may potentiate T-20.
Heredia
Alonso
A
Institute of Human Virology, University of Maryland, 725 W. Lombard Street, Baltimore, MD 21201, USA.
Gilliam
Bruce
B
DeVico
Anthony
A
Le
Nhut
N
Bamba
Douty
D
Flinko
Robin
R
Lewis
George
G
Gallo
Robert C
RC
Redfield
Robert R
RR
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D006801:Humans; D010446:Peptide Fragments / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000276:immunology*; D014779:Virus Replication / Q000187:drug effects
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D019713:Receptors, CCR5; D000077560:Enfuvirtide