AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 22, Number 8, 2006, pp. 763–769 © Mary Ann Liebert, Inc. Interaction of Macrophages with Apoptotic Cells Enhances HIV Type 1 Replication Through PGE 2 , PAF, and Vitronectin Receptor ROSANGELA G. LIMA, 1,3, * LETÍCIA MOREIRA, 3, * JOANA PAES-LEME, 3 VICTOR BARRETO-DE-SOUZA, 3 HUGO C. CASTRO-FARIA-NETO, 2 PATRÍCIA T. BOZZA, 2 and DUMITH CHEQUER BOU-HABIB 3 ABSTRACT Phagocytosis of apoptotic cells by macrophages increases secretion of soluble mediators and generates an antiinflammatory environment. We previously reported that phagocytosis of apoptotic cells by HIV-1-infected macrophages enhances viral replication, with the participation of the cytokine transforming growth factor- 1 and an integrin receptor. Now, we describe the role of prostaglandin E 2 (PGE 2 ), platelet-activating factor (PAF), and the integrin  V  3 (vitronectin receptor, VnR) in this phenomenon. Exacerbation of HIV-1 growth induced by phagocytosis of apoptotic cells was inhibited when HIV-1-infected macrophages were treated with a cyclooxygenase 2 inhibitor, or with a PAF receptor antagonist (BN 52021) immediately after macrophage interaction with apoptotic cells. Treatment of HIV-1-infected macrophages with BN 52021 decreased viral replication, whereas addition of PGE 2 or PAF to these cells enhanced viral replication. Monoclonal antibod- ies (MAbs) to VnR reduced the macrophage uptake of apoptotic cells, prevented the enhancement of HIV-1 growth upon the engulfment of apoptotic cells, and potently augmented viral replication in HIV-1-infected macrophages in the absence of apoptotic cells. In conclusion, PGE 2 and PAF, and ligation of VnR as well, contribute to amplify viral growth in HIV-1-infected macrophages upon uptake of apoptotic cells. 763 INTRODUCTION C ELLS FROM THE MONOCYTE/MACROPHAGE LINEAGE and CD4 + T lymphocytes are the main targets of the human immunodeficiency virus type 1 (HIV-1), the etiological agent of the acquired immunodeficiency syndrome (AIDS). Although most of the circulating HIV-1 isolates are released from acti- vated CD4 + T lymphocytes, these cells are rapidly destroyed by the virus, whereas macrophages are resistant to HIV-1-me- diated cytopathicity. 1 Indeed, chronically infected macrophages can survive for longer periods, sustaining productive viral repli- cation and, thus, functioning as an important reservoir for HIV- 1 infection. 2 Production and release of HIV-1 by macrophages can be influenced by many factors in tissues where macro- phages populate and exert their physiologic activities, such as in the lymph nodes. Accordingly, increased permissiveness of macrophages to HIV-1 infection and higher numbers of HIV- 1-infected and virus-producing macrophages have been associ- ated with a number of conditions, such as coinfections 3–5 and immune activation. 6,7 In this sense, we indicated that the phago- cytosis of apoptotic cells by HIV-1-infected macrophages re- sulted in an exacerbated viral growth, a phenomenon involving the cytokine transforming growth factor 1 (TGF-1) and an integrin receptor, 8 suggesting that HIV-1 replication could be up-modulated in patients when apoptotic cells are cleared by HIV-1-infected macrophages. Production of TGF-1 by HIV- 1-infected macrophages exposed to apoptotic cells was ele- vated, and neutralizing antibodies to TGF-1 reduced by 50% the enhancement effect of apoptotic cells on viral growth. Since TGF-1 is only partially responsible for the augmented HIV-1 replication in this model, other modulators could possibly par- ticipate in the increment of viral growth. 1 Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador, BA, Brazil. 2 Laboratório de Imunofarmacologia, Departamento de Fisiologia e Farmacodinâmica and 3 Laboratório de Imunologia Clínica, Departamento de Imunologia, Instituto Oswaldo Cruz/FIOCRUZ, Rio de Janeiro, RJ, Brazil. *R.G. Lima and L. Moreira contributed equally to this work.