Dendritic cell-T-cell interactions support coreceptor-independent human immunodeficiency virus type 1 transmission in the human genital tract

Worldwide, human immunodeficiency virus (HIV) is transmitted predominantly by heterosexual contact. Here, we investigate for the first time, by examin ing mononuclear cells obtained from cervicovaginal tissue, the mechanisms w hereby HIV type 1 (HIV-1) directly targets cells from the human genital tra ct, In contrast to earlier findings in mucosal models such as human skin, w e demonstrate that the majority of T cells and macrophages but none or few dendritic cells (DC) express the HIV-1 coreceptor CCR5 in normal human cerv icovaginal mucosa, whereas all three cell types express the coreceptor CXCR 4, To understand the role of coreceptor expression on infectivity, mucosal mononuclear cells were infected with various HIV-1 isolates, using either C CR5 or CXCR4, Unstimulated T cells become rapidly, albeit nonproductively, infected with R5- and X4-tropic variants. However, DC and T cells form stab le conjugates which permit productive infection by viruses of both corecept or specificities, These results indicate that HIV-1 can exploit T-cell-DC s ynergism in the human genital tract to overcome potential coreceptor restri ctions on DC and postentry blocks of viral replication in unactivated T cel ls. Thus, mononuclear cells infiltrating the genital mucosa are permissive for transmission of both R5- and X4-tropic HIV-1 variants, and selection of virus variants does not occur by differential expression of HIV-1 corecept ors on genital mononuclear cells.