soluble cd4 and cd4-mimetic compounds inhibit hiv-1 infection by induction of a short-lived activated state可溶性cd4和cd4-mimetic化合物抑制hiv - 1感染的感应短暂的激活状态.pdf

Soluble CD4 and CD4-Mimetic Compounds Inhibit HIV-1 Infection by Induction of a Short-Lived Activated State 1 1 1 1 2 1 1 Hillel Haim , Zhihai Si , Navid Madani , Liping Wang , Joel R. Courter , Amy Princiotto , Aemro Kassa , 1 1 1 1 2 Marciella DeGrace , Kathleen McGee-Estrada , Megan Mefford , Dana Gabuzda , Amos B. Smith III , Joseph Sodroski1,3* 1 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Division of AIDS, Harvard Medical School, Boston, Massachusetts, United States of America, 2 Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 3 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America Abstract Binding to the CD4 receptor induces conformational changes in the human immunodeficiency virus (HIV-1) gp120 exterior envelope glycoprotein. These changes allow gp120 to bind the coreceptor, either CCR5 or CXCR4, and prime the gp41 transmembrane envelope glycoprotein to mediate virus–cell membrane fusion and virus entry. Soluble forms of CD4 (sCD4) and small-molecule CD4 mimics (here exemplified by JRC-II-191) also induce these conformational changes in the HIV-1 envelope glycoproteins, but typically inhibit HIV-1 entry into CD4-expressing cells. To investigate the mechanism of inhibition, we monitored at high temporal resolution inhibitor-induced changes in the conformation and functional competence of the HIV-1 envelope glycoproteins that immed