The role of integrins in the biology of HIV

Integrins are cell adhesion molecules expressed on all cell types in the human body and present in multicellular organisms as simple as sponges. In the human immune system, the integrins LFA-1 and VLA-4 mediate functions including leukocyte migration and lymphocyte activation. They also play a role in HIV infection. Integrins and other host molecules are present on HIV particles and remain functional. In addition, LFA-1 appears to be important in HIV transmission: monoclonal antibodies (MAb) against LFA-1 block HIV-induced syncytia and enhance neutralization by AIDS plasma and by anti-gp120 monoclonal antibodies. To extend these previous findings, two lines of investigation were undertaken: (1) We examined functional LFA-1 and VLA-4 on R5 and X4 virus particles using ICAM-Ig and VCAM-Ig constructs in a solid-phase assay. Given the evidence for the budding of HIV from lipid rafts, and the requirement for intact lipid rafts in integrin binding, we examined whether virus-associated LFA-1 and VLA-4 require intact lipid rafts. We found that virus-associated integrin adhesion was only modestly affected by the disruption of lipid rafts. (2) We characterized the inhibition of HIV infection in primary cells by an anti-LFA-1 MAb. We found that anti-LFA-1 MAb did not block virus attachment, entry, or output. Instead, inhibition was accompanied by caspase 8 activity and was not present with caspase inhibitors. In addition, HIV-infected cells treated with anti-LFA-1 MAb showed higher levels of cell death. These results suggest that anti-LFA-1 MAb blocks HIV infection by inducing apoptosis. Together, these findings provide new insights into the role of adhesion molecules in HIV infection.