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.

The identification of a novel role for annexin II as a cellular cofactor in HIV-1 entry/fusion has implications for specific antiviral strategies, albeit primarily targeting macrophage infection. Nonetheless, as macrophages may contribute to initial viral selection, dissemination, and transmission of virus to CD4 Ï© T cells, and serve as long-term covert reservoirs of HIV-1 (11, 40, 46) , this would be an enviable goal. Particularly evident is the enormous viral burden in macrophages in later stage HIV-1/AIDS during opportunistic infections (12, 21, 22) . Further unraveling of the complex interplay between viral envelope and macrophage membrane constituents remains crucial to the development of antiviral agents active before permanent viral integration into the host cell genome when the virus is most vulnerable. The persistence of HIV-1 infection, coupled with its incredible mutation rate and insular reservoirs, focuses attention on host cell constituents usurped by the virus as potential intervention targets. In this regard, annexin II, a host cell molecule that the virus has appropriated for easing its entrance into the host cell, represents a likely candidate, and SLPI, an endogenous ligand for annexin II, or other annexin II-specific blockades, may represent a therapeutic impediment to the infection process. Clearly, viral pathogens other than HIV-1, including CMV and respiratory syncytial virus (19, 20) , also take advantage of target cell annexin II to enhance their infectivity and/or dissemination, and furthermore, bacteria trigger annexin II recruitment to their attachment sites (27) , all suggesting its broader involvement in microbial entrance and pathogenesis. ter) for helpful advice and support. The authors also thank Robert W. St. G. Fisher, IV (Virology Division, USAMRIID) for Ebola virus assays, Dr. Chris Tseng (National Institute of Allergy and Infectious Diseases [NIAID] Preclinical Antiviral Testing Service), the AACF Compound Screening Program, Dr. Cecil Kwong (Southern Research Institute) for SARS assays, and Drs. Edward Berger and Johnan Kaleeba (NIAID, NIH) for assistance with the vaccinia-based reporter gene fusion assays.