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To the Editor: Discontinuation of combined antiretroviral therapy (CART) improves virological control and specific immunity in some persons infected with human immunodeficiency virus 1 (HIV-1),¹ whereas in others it results in rapid viral rebound and decrease in the antiviral cytotoxic T cell responses below the pretherapeutic level.² The host factors responsible for these opposite consequences are largely unknown. We have recently reported that the mean number of CCR5 coreceptors at the surface of CD4 T cells (CCR5 density) is logarithmically correlated with viral load³ and disease progression⁴ during HIV-1 infection. We have explained this link by showing in vitro that CCR5 density strongly determines the efficiency of HIV-1 life cycle, particularly at the reverse transcription stage.⁵ Herein we report a test of the hypothesis that CCR5 density, which is stable over time in a given individual but varies among individuals, might determine the intensity of viral rebound after cessation of CART.

Methods
We used quantitative flow cytometry³ to measure CCR5 density on peripheral blood CD4 T cells of all chronically infected patients in our clinic who stopped antiretroviral multitherapy in an 18-month period because of physical or psychological drug intolerance (8 women and 15 men). All had CD4 T cell counts ranging from 300 to 1739 and HIV-1 RNA plasma levels below 200 copies/mL. We also measured virus load at day 30 after discontinuation of CART.

Results
Figure 1 shows a strong logarithmic relation (r = 0.644, P = .001) between CCR5 expression and plasma level of HIV-1 RNA. Interestingly, beyond a threshold of 8000 CCR5 molecules per CD4 T cell, virus load rebounded above 100 000 copies/mL.

View larger version (20K): [in this window] [in a new window] Figure. Correlation Between the Mean Number of CCR5 Molecules at the Surface of Peripheral Blood CD4 T Cells and HIV-1 RNA Plasma Level on Day 30 After Interruption of Antiretroviral Treatment HIV indicates human immunodeficiency virus. Curved line indicates the best exponential fit for the data.

Comment
These results emphasize the notion that CCR5 density is related to in vivo virus production and may explain why virus loads before CART and after cessation of CART are comparable. Moreover, they suggest CCR5 density as a predictive factor of the effect of treatment interruption, and emphasize the possible therapeutic potential of agents that would antagonize CCR5.

Jacques Reynes, MD, PhD; Vincent Baillat, MD
Service des Maladies Infectieuses et Tropicales
Hôpital Gui de Chauliac

Pierre Portales, PharmD; Jacques Clot, MD, PhD
Laboratoire d'Immunologie
Hôpital Saint Eloi

Pierre Corbeau, MD, PhD
Institut de Génétique Humaine
Montpellier, France

1. Montaner LJ. Structured treatment interruptions to control HIV-1 and limit drug exposure. Trends Immunol. 2001;22:92-96. FULL TEXT | WEB OF SCIENCE | PUBMED 2. Oxenius A, Price DA, Günthard HF, et al. Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection. Proc Natl Acad Sci U S A. 2002;99:13747-1352. FREE FULL TEXT 3. Reynes J, Portales P, Segondy M, et al. CD4+ T cell surface CCR5 density as a determining factor of viral load in HIV-1-infected individuals. J Infect Dis. 2000;181:927-932. FULL TEXT | WEB OF SCIENCE | PUBMED 4. Reynes J, Portales P, Segondy M, et al. CD4 T cell surface CCR5 density as a host factor in HIV-1 disease progression. AIDS. 2001;15:1627-1634. FULL TEXT | WEB OF SCIENCE | PUBMED 5. Lin Y-L, Mettling C, Portales P, Reynes J, Clot J, Corbeau P. Cell surface CCR5 density determines the postentry efficiency of R5 HIV-1 infection. Proc Natl Acad Sci U S A. 2002;99:15590-15595. FREE FULL TEXT

Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.

JAMA. 2004;291:46.

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