# Comprehensive Insights into the Molecular Basis of HIV Glycoprotein
## 2 Proteins Engaged in HIV Entry
### gp41  
The viral lipid envelopes establish binding with host cell membranes primarily through the gp41 TM glycoprotein. The gp41 subunit comprises approximately 345 amino acids. It is organized into three main domains: a TMD spanning 21 amino acid residues, an extracellular domain (or ectodomain) containing 172 amino acid residues, and a C-terminal CT consisting of 142 amino acid residues, as shown in Figure 5[106]. The ectodomain harbors a pivotal fusion determinant comprised of distinct components: a poly region, a hydrophobic fusion peptide positioned at the N-terminus, the MPER abundant in tryptophan residues, and two hydrophobic heptad-repeat regions referred to as HR1 and HR2 (also called N-helix and C-helix, respectively). These elements collaborate to form \(\alpha\)-helical coiled-coil structures, playing a crucial role in mediating the fusion process necessary for viral entry into host cells [107]. The fusion process is primarily driven by the interaction between HR1 and HR2, facilitated by a disulfide bridge within a hydrophilic loop. In typical gp120 and gp41 quaternary complexes, the fusion peptide is concealed. However, upon binding gp120 to CD4 and coreceptor, the fusion peptide is exposed, leading to membrane destabilization. Subsequently, the fusion pore is formed, allowing the fusion peptide to penetrate tissues [108; 109]. Each trimer consists of three HR1 motifs aligned in parallel, folding over an antiparallel hydrophobic groove with three HR2 domains, culminating in forming a stable six-helix bundle capable of facilitating fusion [110]. Cellular fusion proteins, such as SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) and other viral fusion proteins, form prompt fusion mechanisms via gp41 [31]. HR1 and HR2 peptides can obstruct the formation of the gp41 six-helix bundle. HIV-1-infected individuals can employ HR2-derived peptides like enfuvirtide (Fuzeon or T-20) for therapeutic intervention; however, due to its elevated cost and limited oral bioavailability, its clinical applicability is restricted. The gp41 extracellular domain encompasses 24 amino acids in the MPER. Although the precise mechanism through which this region fosters membrane fusion remains elusive, it is imperative for fusogenicity and virus propagation. Neutralizing antibodies such as 2 FS, 4E10, and Z13 target the highly conserved MPER region [110]. The Env protein is anchored to the lipid bilayer by the gp41 TMD, which comprises approximately 25 conserved amino acids. Mutations within the \"core\" region of the gp41 TMD can influence Env-mediated fusion due to this domain's high degree of conservation [111]. Traditionally, the topology of gp41 suggests that the TMD forms a single \(\alpha\)-helix spanning the membrane, while the CT resides within the viral particle (Figure 5, left). Alternative topologies, proposing that gp41 spans the membrane three times (initially based on monoclonal antibodies targeting an epitope within the gp41 CT), have also been suggested (Figure 5, right, known as the \"Kennedy\" sequence (KS)) [112]. Findings by [PERSON] et al. demonstrate that the LLP2 region in the gp41 CT may occasionally become exposed on the cell surface during cell fusion [113]. Due to its critical role in the fusion process, LLP2 is considered a promising target for antiviral therapies, as disrupting its interactions could prevent HIV-1 from successfully merging with host cells and thereby inhibit infection. Located in the cytoplasmic domain alongside other lytic peptide regions like LLP1 and LLP3, LLP2 is characterized by amphipathic helices facilitating lipid bilayer interactions. This membranous region influences the fusogenic activity of gp41 by interacting with both the viral core and host membranes, thereby regulating fusion efficiency. The surface-exposed nature of LLP2 allows it to modulate interactions within the gp41 structure, optimizing conditions for viral entry [114; 115].