The paucity of virus-laden CD4+ cells in individuals infected with human immunodeficiency virus type-1 (HIV-1) contrasts with the greatly reduced numbers and function of these lymphocytes. A pathway is described whereby dendritic cells carry HIV-1 to uninfected T cells, amplifying the cytopathic effects of small amounts of virus. After exposure to HIV-1, dendritic cells continue to present superantigens and antigens, forming clusters with T cells that are driven to replicate. Infection of the dendritic cells cannot be detected, but the clustered T cells form syncytia, release virions, and die. Carriage of HIV-1 by dendritic cells may facilitate the lysis and loss of antigen specific CD4+ T cells in acquired immunodeficiency syndrome.

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SlllnmaryA procedure has been developed to isolate dendritic cells to a high degree of purity from fresh blood. Prior enrichment methods have relied upon an initial 1-2-d culture period. Purified fresh isolates lack the characteristic morphology, phenotype, and immunostimulatory function of dendritic cells. The purified cells have the appearance of medium sized lymphocytes and express substantial levels of CD4, but lack the T cell molecules CD3, CDS, and T cell receptor. When placed in culture, the cells mature in a manner resembling the previously described, cytokine-dependent maturation of epidermal dendritic cells (Langerhans cells). The ceils enlarge and exhibit many cell processes, express much higher levels of major histocompatibility complex class II and a panel of accessory molecules for T cell activation, and become potent stimulators of the mixed leukocyte reaction. Among the many changes during this maturation process are a fall in CD4 and the appearance of high levels of B7/BB1, the costimulator for enhanced interleukin 2 production in T cells. These changes are not associated with cell proliferation, but are dependent upon the addition of monocyte-conditioned medium. We suggest that the freshly isolated CD4-positive blood dendritic cells are recent migrants from the bone marrow, and that subsequent maturation of the lineage occurs in tissues in situ upon appropriate exposure to cytokines.

SummaryEarlier work has identified a cell population that replicates HIV-1 in the absence ofstandard T cell stimuli . The system consists of dendritic cells and memory T lymphocytes that emigrate from organ cultures of human skin and together support a productive infection with HIV-1 . These emigrants resemble cells that can be found in mucous membranes and that normally traffic in afferent lymph . Here, we report that a low level of infection in the dendritic cell can initiate extensive HIV-1 replication in cocultures with T cells . First we extended our earlier work to larger skin specimens from cadavers . As long as the organ cultures were set up within 36 h of death, the emigrant leukocytes were comparable to cells from fresh surgical specimens in number, phenotype, and function . These mixtures of dendritic cells and T cells provided the milieu for a productive infection with several virus isolates . When purified dendritic cells were separately pulsed with virus and then mixed with T cells that had not been pulsed with HIV-1, active infection ensued. The infectivity of HIV-pulsed dendritic cells persisted for at least 1 .5 d in culture, but was blocked if AZT was added during that time to block reverse transcription in the dendritic cells . The number of copies of proviral DNA in the dendritic cells corresponded to < 100 copies per 5 X 104 cells, but upon mixing with T cells, > 104 copies were found 5-7 d later. By contacting syngeneic T cells, extralymphoid depots of dendritic cells-even with a low viral burden as has been reported in vivo-may contribute to chronic HIV-1 replication in infected individuals .

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