Decreased resistance to infection with viruses

Studies which have been performed with in vitro models of infection have yielded results consistent with those obtained with in vivo models. In vitro studies have included the use of fully constituted primary cell populations such as splenocytes as well as purified macrophages and lymphocytes from rodents and humans. Immortalized continuous cell types which exhibit macrophage-like or T lymphocyte-like properties also have been employed. Cabral and Vasquez (1991, 1992) reported that THC affects the capacity of macrophages to respond to herpes simplex viruses in culture. THC (10-5 M-10-7M) exerted a dose-dependent effect on macrophage extrinsic antiviral activity to HSV-2 (Figure 9.2), an activity which is characterized by the ability of macrophages to restrict the replication of viruses in adjacent unin-fected permissive xenogeneic cells in an interferon-independent fashion (Morahan et al., 1977). The inhibitory effect was exerted on a variety of murine macrophage-like cells including RAW264.7, J774A.1, and P388D1. The macrophage-like cells regained their extrinsic antiviral activity in a time-related fashion following removal of THC. In contrast, THC had no effect on intrinsic antiviral activity, an activity which is characterized by the capacity of macrophages to ingest and degrade virus and thereby maintain a nonpermissive state for productive virus infection (Stevens and Cook, 1971; Selgrade and Osborne, 1974). THC has been demonstrated also to decrease cytotoxic T lymphocyte (CTL) activity against herpes simplex virus type 1 (HSV-1) (Fischer-Stenger, Updegrove and Cabral, 1992). Spleen cells from C3H/HeJ (H-2k) mice primed with HSV-1 and administered THC (15mg/kg and 100mg/kg) were deficient in cytolytic activity against HSV-1-infected murine L929 (H-2k) target cells in vitro. In their experiments, THC in vivo exposure had little effect on the number of T lymphocytes expressing the Lyt-2 or L3T4 antigens. Furthermore, Nomarski optics microscopy revealed that the CTLs from the drug-treated, virus-primed mice were able to bind specifically to HSV-1-infected target cells. THC affected CTL cytoplasmic polarization and granule reorientation toward the CTL-virus-infected cell interface. It was concluded that THC elicited dysfunction in CTLs by altering effector cell-target cell postconjuga-tion events resulting in failure of delivery of "lethal hit" molecules to the virus-infected cells.

0 0

Post a comment