Human Immunodeficiency Virus (HIV) is a diploid, C-type enveloped retrovirus belonging to the Lentivirus genus, characterized by two positive-sense single-stranded RNA genomes, that transitioned from non-human primates to humans and has become globally widespread. In its advanced stages, HIV leads to Acquired Immune Deficiency Syndrome (AIDS), which severely weakens the immune system by depleting CD4+ helper T cells. Without treatment, HIV progressively impairs immune function, making the body susceptible to various opportunistic infections and complications, including cardiovascular, respiratory, and neurological issues, as well as secondary cancers. The envelope glycoprotein complex (Env), composed of gp120 and gp41 subunits derived from the precursor gp160, plays a central role in cycle entry. gp160, synthesized in the rough endoplasmic reticulum, undergoes glycosylation and proteolytic cleavage, forming a trimeric spike on the virion surface. These structural features, including the transmembrane domain (TMD), membrane-proximal external region (MPER), and cytoplasmic tail (CT), are critical for viral infectivity and immune evasion. Glycosylation and proteolytic processing, especially by furin, are essential for Env’s fusogenic activity and capacity to evade immune detection. The virus’s outer envelope glycoprotein, gp120, interacts with host cell CD4 receptors. This interaction, along with the involvement of coreceptors CXCR4 and CCR5, prompts the exposure of the gp41 fusogenic components, enabling the fusion of viral and host cell membranes. While this is the predominant pathway for viral entry, alternative mechanisms involving receptors such as C-type lectin and mannose receptors have been found. This review aims to provide an in-depth analysis of the structural features and functional roles of HIV entry proteins, particularly gp120 and gp41, in the viral entry process. By examining these proteins’ architecture, the review elucidates how their structural properties facilitate HIV invasion of host cells. It also explores the synthesis, trafficking, and structural characteristics of Env/gp160 proteins, highlighting the interactions between gp120, gp41, and the viral matrix. These contributions advance drug resistance management and vaccine development efforts.
