Secretory Leukocyte Protease Inhibitor Binds to Annexin II, a Cofactor for Macrophage HIV-1 Infection

Ma, Ge; Greenwell-Wild, Teresa; Lei, Kejian; Jin, Wenwen; Swisher, Jennifer; Hardegen, Neil; Wild, Carl T.; Wahl, Sharon M.

Annexin II may represent a molecular pathway exploited by HIV-1 unique to macrophage hosts and thus, a potential target to block their virus susceptibility. Both laboratoryadapted and clinical M tropic isolates appear to coopt this host cell bridge into the cell's interior. Whether annexin II selectively boosts the viral entry/fusion process or possibly also influences pathways involved in HIV-1-mediated macrophage signaling, viral DNA transport, or subsequent virion construction, budding and release remains to be deciphered. Annexin II has the potential to traverse into intracellular compartments and interaction of annexin II with the actin cytoskeleton may not only facilitate internalization, but also the trafficking of HIV-1 within the cell and/or represent the scaffolding for viral transcription (30) . Nonetheless, our data support a dominant role of annexin II to be in the early steps of the infection process, preceding reverse transcription. Annexin II may represent one of multiple potential cofactors, such as syndecan and human neutrophil elastase (31, 32) , which independently or collaboratively might be usurped by HIV-1 to facilitate the infectious process. Because annexin II is a membrane-associated protein, best known as a docking station for tissue plasminogen activator/plasminogen (16) , it is unclear if it transduces a signal because it lacks a hydrophobic signal sequence, but conceivably, may serve as an adaptor in a signaling cascade. Annexin II can be phosphorylated at key residues by several kinases, including the src oncogene (17) and Pyk-2 (15), a tyrosine kinase activated by HIV-1 (33, 34) , but such a pathway awaits delineation. Although less persuasive due to the temporal association of SLPI/anti-annexin II inhibition with preintegration events, SLPI may also influence NF-B activation and/or proteasome inhibition (6, 8) , both of which are requisite in an optimal infection process (35) (36) (37) .