Recent Advances in Understanding the Molecular Mechanisms of HIV-1 Entry and Fusion: Revisiting Current Targets and Considering New Options for Therapeutic Intervention

Ingrid      Markovic; Kathleen   A.   Clouse

Abstract

Recent advances in our understanding of the cellular and molecular mechanisms of HIV-1 entry provide the basis for novel therapeutic strategies that prevent viral penetration of the target cell-membrane, while reducing detrimental virus and treatment effects on cells and prolonging virion exposure to immune defenses. A number of potential sites for therapeutic intervention become accessible during the narrow window between virus attachment and the subsequent fusion of viral envelope with the cell membrane. Initial approaches considered for prevention of HIV-1 entry included the use of natural ligands, small-molecule inhibitors and / or monoclonal antibodies, which could interfere with gp120-CD4 and / or gp120-CXCR4 / CCR5 interaction. Others avenues pursued were the use of agents that interfere with the conformational changes of gp120 or gp41 leading to subsequent fusion of viral and cellular membranes. More recently, strategies have emerged that involve inhibition of thiol / disulfide oxidoreductases (factors which facilitate Env transition from an inactive to a fusion-competent conformation) to block redox exchange, thereby impeding the entry process. This review provides a summary of the cellular and viral factors mediating the HIV-1 entry process, with an emphasis on novel therapeutics targeting Env-receptor / coreceptor interaction, Env conformational change and the membrane fusion process.

Keywords: hiv-1 pathogenesis, antiviral therapy, viral entry, membrane fusion, thiol/disulfide exchange, envelope, glycoprotein, conformational restructuring, cd4, ccr5, cxcr4