IFN--activated monocytes weakly produce HIV-1 but induce the recruitment of HIV-sensitive T cells and enhance the viral production by these recruited T cells He ´la Saı¨di, 1 Giuliana Magri, Cedric Carbonneil, Nadine Nasreddine, Mary Re ´ quena, and Laurent Be ´ lec Universite ´ Paris V, Unite ´ INSERM U743 “Immunologie Humaine,” Equipe “Immunite ´ et Biothe ´rapie Muqueuse,” Centres de Recherches Biome ´dicales des Cordeliers, Paris, France Abstract: The ability of macrophages to adapt to changing cytokine environments results in the dominance of a particular functional phenotype of macrophages, which would play a significant role in HIV pathogenesis. In comparison with untreated macrophages (M0), we examined the role of mac- rophages derived from IFN--activated monocytes (M1) in the HIV spread. We show that M0 and M1 bind with the same efficiency as HIV-1 with a pre- dominant role of C-type lectins in the R5-HIV at- tachment and of the heparan sulfate proteoglycans in the X4-HIV attachment. Despite similar levels of R5- and X4-HIV DNA, M1 replicates and weakly transmits the virus to activated T cells by releasing CXCR4- and CCR5-interacting chemokines. The blockade of dendritic cell-specific ICAM-3-grab- bing nonintegrin expressed on M1 by mAb does not interfere with the viral transfer. Uninfected M1 recruits HIV-sensitive T cells efficiently and re- leases soluble factors, enhancing the viral produc- tion by these recruited cells. This study highlights the role of IFN- to induce a population of macro- phages that archive HIV-1 within a latent stage and cause the persistence of the virus by favoring the recruitment of T cells or enhancing the viral rep- lication in infected CD4  T cells. J. Leukoc. Biol. 80: 000 – 000; 2006. Key Words: adsorption  infection  transfer  cytokines  chemo- kines INTRODUCTION Macrophages play a central role in defense and in the control of infections by destroying invading pathogens directly or by secreting cytokines able to activate other arms of the innate or adaptive immune response. In HIV infection, macrophages are thought to play an ambiguous role acting as an antiviral de- fense system or as target cells. Macrophages may serve as sites for virus replication at late stages of AIDS when CD4 + T cells are depleted markedly or following withdrawal of viral inhibitor treatment [1, 2]. Moreover, their interplay, as APCs or a source of chemotactic cytokines, with CD4 + T cells may favor inter- cell virus transmission [3]. Indeed, there is increasing interest in several aspects of macrophage infection, including the mechanism of HIV infection and their role in the pathogenesis of disease. In response to changes in cytokine environment, macro- phages can reversibly shift their functional phenotype through a multitude of patterns. This capacity of macrophages to re- spond specifically at microenvironment changes has important implication for therapeutic targeting of macrophages in chronic disease, which results in the dominance of particular func- tional phenotypes of macrophages [4 – 6]. It is well known that the early phase of HIV infection, which involves activation of T cells, is regulated by Th1 cytokines exemplified by IL-2 and IFN-, which may favor virus replication in CD4 + T cells [7]. Elevated levels of plasma IFN- were also detected in patients with HIV-1 in the absence of concurrent, opportunistic infec- tions, and a high number of IFN--producing cells were de- tected in the peripheral blood compartment and in the germinal centers of lymph nodes during HIV disease [8]. We focused herein on two key questions we consider criti- cal: How do changes in macrophages derived from IFN-- activated monocytes influence their ability to be infected and to support viral replication? and How do changes in cytokines/ chemokines released by macrophages derived from IFN-- activated monocytes create an environment that would support the spread of HIV by implicating HIV-1-sensitive T cells? To this end, we first evaluated whether the activation of monocytes by IFN- influenced the susceptibility of macrophages to HIV entry and the establishment of a productive infection. We evaluated the viral attachment that determines their ability to capture the virus and the intensity of viral replication by using the real-time PCR to quantify the viral DNA and the p24 ELISA as an indicator of virus production and spread capacity. According to a previous study, the HIV entry into macrophages and CD4 + T cells is mediated by interaction of the virus envelope with CD4 and CXCR4 [9] or CCR5 [10, 11]. Virions 1 Correspondence: Centre de Recherches Biome ´dicales des Cordeliers, Unite ´ INSERM U743 Equipe “Immunite ´ et Biothe ´rapie Muqueuse,” 15 rue de l’Ecole de Me ´decine, 75270 Paris, Cedex 06, France. E-mail: hela.saidi@u430.bhdc.jussieu.fr Received April 18, 2006; revised July 19, 2006; accepted August 7, 2006; doi: 10.1189/jlb.0406278. 0741-5400/06/0080-0001 © Society for Leukocyte Biology Journal of Leukocyte Biology Volume 80, December 2006 1 Uncorrected Version. Published on September 13, 2006 as DOI:10.1189/jlb.0406278 Copyright 2006 by The Society for Leukocyte Biology.