HIV-1 INFECTION ALTERS MONOCYTE INTERACTIONS WITH HUMAN MICROVASCULARENDOTHELIAL-CELLS

HIV infection of monocytes resulted in a twofold elevation of adhesion molecule LFA-1 (both alpha(L)/CD11a and beta(2)/CD18 subunits) and LF A-3 (CD58), with no apparent increase in LFA-2 (CD2) or various beta(1 )-integrins. Homotypic aggregation of monocytes was evident 2 h after exposure to virus and was inhibited by mAbs to both the alpha(L)- and beta(2)-subunits of LFA-1. HIV-infected monocytes also showed a marked increase in adherence to human capillary endothelial cell monolayers derived from brain, lung, and skin. This adherence was inhibited by mA b to either LFA-1 subunit and by mAb to the counter-receptor intercell ular adhesion molecule-1. Cocultivation of HIV-infected monocytes with endothelial cells increased permeability of endothelial cell monolaye rs to I-125 albumin in transwell assay systems. The increased endothel ial permeability induced by HIV-infected monocytes was associated with a substantial disruption of the endothelial cell monolayer. Morpholog ic disruption was not a direct toxic effect on endothelial cells, but appeared to be secondary to changes in endothelial cell-cell or cell-m atrix interactions. Northern blot analysis showed increased expression of gelatinase B (92-kDa gelatinase), tissue inhibitor of metalloprote inase TIMP-1, and TIMP-2 in the HIV-infected monocytes. Consistent wit h these Northern analyses, secretion of gelatinase activity in culture fluids of HIV-infected monocytes was also increased and was dependent on the stage of virus replication. Incubation of HIV-infected monocyt es with the proteinase inhibitors TIMP-1 and TIMP-2 inhibited the incr eased permeability of endothelial cell monolayers to I-125 albumin. Th ese results suggest possible mechanisms for extravasation of HIV-infec ted monocytes through vascular endothelium into tissue in early stages of HIV disease.