Published online before print July 15, 2003

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0403187

Received for publication April 25, 2003.
Revised June 16, 2003.
Accepted for publication June 17, 2003.

Article

Macrophages and lymphocytes differentially modulate the ability of RANTES to inhibit HIV-1 infection

Eleanore Gross ^*, Carol A. Amella ^*, Lorena Pompucci ^*, Giovanni Franchin , Barbara Sherry ^*, and Helena Schmidtmayerova ^*@

*Immunology and Inflammation Center, North Shore-LIJ Research Institute, New York, and Department of Medicine, Albert Einstein College of Medicine, New York

^@ To whom correspondence should be addressed. E-mail: HSchmidt{at}nshs.edu.

Abstract

The -chemokines MIP-1, MIP-1, and RANTES inhibit HIV-1 infection of CD4⁺ T cells by inhibiting interactions between the virus and CCR5 receptors. However, while -chemokine-mediated inhibition of HIV-1 infection of primary lymphocytes is well documented, conflicting results have been obtained using primary macrophages as the virus target. Here, we show that the -chemokine RANTES inhibits virus entry into both cellular targets of the virus, lymphocytes, and macrophages. However, while virus entry is inhibited at the moment of infection in both cell types, the amount of virus progeny is lowered only in lymphocytes. In macrophages, early-entry restriction is lost during long-term cultivation, and the amount of virus produced by RANTES-treated macrophages is similar to the untreated cultures, suggesting an enhanced virus replication. We further show that at least two distinct cellular responses to RANTES treatment in primary lymphocytes and macrophages contribute to this phenomenon. In lymphocytes, exposure to RANTES significantly increases the pool of inhibitory -chemokines through intracellular signals that result in increased production of MIP-1 and MIP-1, thereby amplifying the antiviral effects of RANTES. In macrophages this amplification step does not occur. In fact, RANTES added to the macrophages is efficiently cleared from the culture, without inducing synthesis of -chemokines. Our results demonstrate dichotomous effect of RANTES on HIV-1 entry at the moment of infection, and on production and spread of virus progeny in primary macrophages. Since macrophages serve as a reservoir of HIV-1, this may contribute to the failure of endogenous chemokines to successfully eradicate the virus.

Key Words: CCR5 expression • internalization • -chemokine production • MIP-1 • MIP-1

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