In This Issue

(See article on pages 183–192.)

Pathological inflammation, such as occurs in allergic contact dermatitis and delayed-type hypersensitivity, requires migration into the inflamed region of lymphocytes and granulocytes, as well as dendritic cells (DCs) and other antigen-presenting cells (APCs). Adhesive interactions of these migratory cells with the vascular endothelium and with other cell types and extracellular macromolecules must therefore be tightly regulated. The integrin β2 subunit, also called CD18, is found in several heterodimeric forms that are expressed by myeloid cells and is central to many of these interactions. The importance of CD18 in host defense is evident because patients with leukocyte adhesion deficiency type I (LAD I), who carry mutations in the corresponding human gene, are prone to bacterial infection. Grabbe et al. now report that in a mouse knockout model lacking CD18 entirely, animals are unable to mount the usual inflammatory responses to allergens. At the cellular level, the defect is specific for the extravasation of T cells, since APCs migrate normally into areas exposed to allergen. These findings generally confirm cell culture and intravital microscopic studies indicating that β1 integrins can substitute for β2 in monocytes and DCs but not in lymphocytes. Interestingly, CD18-deficient T cells appear to be spontaneously hyperactivated, suggesting that adhesion through CD18 helps suppress autoimmune activation. For more on regulation of the T cell response by integrins, see the Perspective by Billadeau and Leibson, as well as other articles in the ongoing series on signaling in lymphocytes.

(See article on pages 205–211.)

Women are at risk of infection from HIV-positive male partners not only because they can become exposed to free viral particles, but also because infected cells, primarily macrophages and T cells, occur in the semen of infected men. The relative importance of cell-associated and cell-free virus for male-to-female transmission of AIDS has been controversial, and even the route by which cell-associated virus reaches new target cells is far from clear. Arguing that these difficulties reflect the absence of a suitable in vivo model system for this route, Khanna et al. have explored the course of infection following exposure to cell-associated HIV in the mouse. Normal mouse leukocytes are unaffected by the presence of HIV, but the authors show that female SCID mice reconstituted with human leukocytes can be infected after intravaginal inoculation with peripheral blood leukocytes (PBLs) derived from HIV-positive individuals. In this system, free virus is not transmitted, but PBL-associated HIV can be found in the female animal’s lymph nodes within several hours of inoculation with infected cells. Within two weeks, this cell-associated virus is transmitted to previously uninfected cells. Khanna et al. find that transmission depends on pretreatment with progesterone, which thins the vaginal epithelium, raising the possibility that hormone treatment or cyclical changes in hormones could affect the efficiency of infection by cell-associated virus in women as well. The authors also show that cyclodextrin, an agent that disrupts lipid rafts in cell membranes, prevents HIV transmission in this system. Several mechanisms for this effect could be envisioned and, while these remain to be resolved, the finding establishes that the mouse model system can be exploited to test the effects of various drugs on cell-associated HIV transmission.

(See article on pages 285–286.)

In a recent issue, Mesri et al. reported that the apoptosis inhibiting protein survivin can be inhibited in a wide variety of tumor cells using a dominant negative form of the protein. Survivin is expressed normally in early development and is found in tumors of many sorts, but few healthy adult cell types express it. Cancer cells — especially in larger and more advanced tumors — can become dependent on survivin for their continued proliferation, apparently because this protein abolishes a normal cell-cycle checkpoint and prevents them from being driven toward apoptosis. Zaffaroni et al. now show that hammerhead ribozymes directed at the survivin mRNA have a similar, potentially beneficial effect. Such ribozymes can synergize with a more traditional chemotherapeutic, cisplatin, to kill human melanoma cells in culture. This finding is particularly interesting in light of a recent report in the Journal of the National Cancer Institute (Kanwar, J.R., et al. 2001. 93:1541-1552.), showing that inhibition of survivin using antisense or dominant negative transgenes helps eliminate established lymphomas and prevent the emergence of new tumors in a mouse model. Ribozymes to survivin might therefore be used in a similar manner, probably in conjunction with chemotherapeutic or immunotherapeutic agents, to control human tumors in a clinical setting.