Molecular mechanisms of HIV-1 entry into host cells and emerging therapeutic strategies

Abstract The global HIV/AIDS pandemic continues to pose a major public health challenge, underscoring the need for improved mechanistic understanding of viral infection and therapeutic intervention. HIV-1 infection is initiated by a highly orchestrated entry process that represents the first and most decisive determinant of productive infection. This process begins with binding of the viral envelope glycoprotein gp120 to the CD4 receptor, followed by engagement of the chemokine co-receptors CCR5 or CXCR4, triggering conformational rearrangements that activate gp41-mediated membrane fusion. This review synthesizes current biochemical and structural insights into HIV-1 entry, with emphasis on envelope conformational dynamics, receptor and co-receptor interactions, membrane fusion mechanisms, and host determinants that regulate entry efficiency and tropism. We further examine how these early events shape subsequent post-entry processes, including capsid stability and intracellular trafficking, that are essential for productive infection. Therapeutic strategies targeting viral entry, including attachment inhibitors, fusion inhibitors, co-receptor antagonists, and broadly neutralizing antibodies are critically discussed, alongside emerging challenges such as resistance and viral heterogeneity. Finally, we highlight key knowledge gaps in entry biology, including alternative entry routes and cell-to-cell transmission, and discuss how addressing these may inform next-generation antiviral and preventative strategies.