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CCR5 density levels on primary CD4 T cells impact the replication and Enfuvirtide susceptibility of R5 HIV-1

Heredia, Alonso; Gilliam, Bruce; DeVico, Anthony; Le, Nhut; Bamba, Douty; Flinko, Robin; Lewis, George; Gallo, Robert C; Redfield, Robert R

doi: 10.1097/QAD.0b013e32815278ea
Clinical Science: Concise Communication

Objective and design: 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 ∼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 ∼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.

From the Institute of Human Virology, University of Maryland, Baltimore, Maryland, USA.

Received 5 December, 2006

Revised 20 February, 2007

Accepted 7 March, 2007

Correspondence to R.R. Redfield, Institute of Human Virology, 725 W. Lombard St, Baltimore, MD 21201, USA. Tel: +1 410 706 4613; fax: +1 410 706 1919; e-mail: redfield@umbi.umd.edu

© 2007 Lippincott Williams & Wilkins, Inc.