Experimental and Molecular Pathology 68, 133–138 (2000) doi:10.1006/exmp.1999.2300, available online at http://www.idealibrary.com on Interactions of CCR5 and CXCR4 with CD4 and gp120 in Human Blood Monocyte-Derived Dendritic Cells 1 Xiaodong Xiao,* Audrey Kinter,² Christopher C. Broder,‡ ,2 and Dimiter S. Dimitrov* ,3 *Laboratory of Experimental and Computational Biology, NCI-FCRDC, NIH, Frederick, Maryland 21702-1201; ² Laboratory of Immunoregulation, NIAID, NIH, Bethesda, Maryland 20892; and ‡Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799 Received November 2, 1999 Dendritic cells (DC) and macrophages play an important role in the important for HIV-1 infection, the first central stage in the entry mecha- nism, the formation of gp120–CD4–coreceptor complexes, is not im- generation of immune responses and transmission of HIV infection. It has been recently found that, in the presence of gp120, CD4 can paired except for the formation of the gp120–CD4–CXCR4 complex in macrophages. Therefore, for most CD4+ target cells restraint(s) on be efficiently coimmunoprecipitated by anti-CXCR4 antibodies from lymphocytes and monocytes but not from blood monocyte-derived productive HIV-1 infection appears to occur at stages of the virus life cycle subsequent to the gp120–CD4–coreceptor complex formation. macrophages. The gp120–CD4–CXCR4 complex formation paralleled the ability for these cell types to support X4 (LAV) HIV-1 envelope Key Words: HIV-1; CD4; CXCR4; CCR5; gp120; dendritic cells; membrane fusion. glycoprotein (Env)-mediated fusion. Here we report that, unlike macro- phages but similar to lymphocytes and monocytes, human blood mono- cyte-derived DC allow efficient complex formation among the HIV-1 coreceptor CXCR4, the primary receptor CD4, and the Env gp120 (LAV) which parallels their fusion ability with cells expressing HIV- 1 Env (LAV). In addition, DC behaved similarly to macrophages, INTRODUCTION lymphocytes, and monocytes in their ability to support formation of complexes between CD4 and the other major HIV-1 coreceptor CCR5 even in the absence of gp120 as demonstrated by CD4 coimmunopreci- pitation with anti-CCR5 antibodies. Further, the amount of gp120– Dendritic cells (DC) are the most potent generators of CD4–CXCR4 (or CCR5) complexes was proportional to the extent of primary and secondary immune responses. They are found cell fusion mediated by the HIV-1 Env (LAV or JRFL, respectively). in the dermis, in blood, and in lymphoid tissue, particularly These results demonstrate that of all the major types of host cells in T-cell-rich regions, where they can efficiently deliver virus to CD4+ T cells. However, there has been some controversy 1 The views expressed in the manuscript are solely those of the regarding the ability of HIV-1 to productively infect DC authors, and they do not represent official views or opinions of the Department of Defense or The Uniformed Services University of the although this can be due to the inherent heterogeneity of DC Health Sciences. and the use of different subpopulations in different studies. It 2 To whom correspondence may be addressed. E-mail: cbroder@ was initially found that the virus can replicate in DC (Pat- mxb.usuhs.mil. terson and Knight, 1987; Langhoff et al., 1991) but a later 3 To whom correspondence may be addressed at LECB, NIH, Build- report suggested that the replication in cultured DC is ineffi- ing 469, Room 216, P.O. Box B, Miller Drive, Frederick, MD 21702- 1201. Fax: 301-846-6189. E-mail: dimitrov@ncifcrf.gov. cient although infectious virus can be effectively transmitted 0014-4800/00 133