HIV-1-TAT PROTEIN PROMOTES CHEMOTAXIS AND INVASIVE BEHAVIOR BY MONOCYTES

Monocytes are susceptible to HIV infection and to activation by a regu latory gene product of the HIV genome, HIV-Tat. Recently, we have demo nstrated that treatment with HIV-Tat up-regulates monocyte adhesion to the endothelium and increases metalloproteinase production. In the pr esent study, we have examined the ability of the HIV-Tat protein to al ter the migratory and invasive behavior of monocytes. Monocytes pretre ated for 24 h with 10 ng/ml HIV-Tat exhibited enhanced migratory behav ior compared with untreated monocytes in chemotaxis assays, both in th e absence of a chemoattractant as well as in response to FMLP. In addi tion, HIV-Tat itself induced the migration of both untreated and HIV-T at pretreated monocytes. Checkerboard analysis showed that monocytes m igrated in response to an HIV-Tat concentration gradient, thus confirm ing the chemotactic characteristics of the HIV-Tat protein, Pretreatme nt of monocytes with 10 ng/ml HIV-Tat for 24 h also increased their ab ility to invade reconstituted extracellular membrane (Matrigel)coated filters by 5-fold in the absence of chemoattractant. The presence of F MLP or HIV-Tat further enhanced invasion by both untreated and HIV-Tat -pretreated monocytes by more than 10-fold. Monocyte invasion was part ially inhibited by the inclusion of anti-beta(1) integrin Ab or tissue inhibitor of metalloproteinase (TIMP). Thus, for the first time, we p resent evidence that HIV-Tat can enhance the chemotactic and invasive behaviors of monocytes and propose an active role for HIV-Tat in the r ecruitment of monocytes into extravascular tissues, a process which ma y contribute to the destruction of tissues and cellular architecture o ften seen in patients with acquired immunodeficiency syndrome.