# Comprehensive Insights into the Molecular Basis of HIV Glycoprotein
## 2 Proteins Engaged in HIV Entry
### gp120
In addition to mutations in the V3 loop, modifications in the \"bridging sheet\" region of gp120 can significantly influence how coreceptors interact [96]. Maraviroc, an FDA-approved drug, specifically targets the interaction between the V3 loop of gp120 and the CCR5 coreceptor. It directly binds to CCR5 and prevents the association between gp120 and CCR5 [97]. However, maraviroc is impractical for viruses that utilize the CXCR4 coreceptor, as expected from a drug targeting the CCR5 receptor. Resistance to maraviroc primarily arises from mutations that allow gp120 to effectively engage with drug-bound CCR5 rather than switching to CXCR4. These mutations enable the virus to circumvent the inhibitory effects of maraviroc by maintaining its dependence on the CCR5 coreceptor [97; 98]. Vaccine Research Center (VRC) in NIAID (National Institute of Allergy and Infectious Diseases) has successfully elucidated various structures of HIV-1 gp120 envelope glycoprotein. For instance, one notable structure involves the HIV-1 gp120 \"core\" lacking the V1/V2 and V3 variable loops and the N- and C-termini. This core structure was observed in complex with a neutralizing antibody and fragments of the CD4 receptor [88]; a gp120 core structure with V3 loop, bound to neutralizing antibodies and the CD4 receptor [96]; unliganded CD4-bound HIV-1 gp120 [89]; CD4-binding-site-specific antibodies poorly neutralizing the gp120 core [99]; CD4-binding-site-specific neutralizing antibodies bound to the gp120 core in a CD4-bound conformation [100]; and gp120's core bound to gp41's gp120-interacting region [101]. The research findings provide a detailed understanding of how gp120 interacts with key components involved in HIV-1 entry, including CD4, gp41, coreceptors, entry inhibitors (such as T-20), and neutralizing antibodies. Specifically, gp120's binding to CD4 initiates conformational changes that enable its interaction with coreceptors (CCR5 or CXCR4) and gp41, facilitating membrane fusion and viral entry. Additionally, these interactions expose epitopes on gp120 that are targeted by neutralizing antibodies, making this process critical for developing entry inhibitors and vaccines (as shown in Figure 4) [102; 103; 104; 105; 88]. In contrast to unbound gp120 CD4-bound structures, the binding of CD4 triggers a significant structural rearrangement in gp120. Post-CD4 binding, previously spatially distant residues undergo conformational changes to form the coreceptor binding surface [87]. When the viral complex interacts closely with the target cell, steric hindrance impedes the efficient access of neutralizing antibodies. This action enables the virus to delay exposure of the vulnerable coreceptor binding surface. Models depicting gp120 trimers in unbound and CD4-bound states can be generated using X-ray data and electron tomography maps (Figure 4c,d) [62]. These structural investigations suggest that HIV-1 Env glycoproteins are highly adapted to conceal critical functional surfaces from antibody recognition while maintaining flexibility and tolerance to sequence variations to evade immune responses. gp120 engages the CD4 receptor via the CD4 binding site located on its surface. This binding site predominantly comprises conserved regions between the \(\beta\) inter-domain sheet and two domains of gp120. Positioned on the opposite side of the HLA type II binding domain within the D1 domain of the Complementarity Determining Region 2 (CDR2) loop, the CD4 binding domain plays a pivotal role. Residues Phe43 and Arg59 are particularly crucial, as they establish significant interactions with the residues Glu370, Trp427, and Asp368 within the CD4 binding site of gp120. The varying affinity of HIV Env for CD4 is contingent upon factors such as tropism and the monomeric or oligomeric quaternary structures. Moreover, the flexibility of gp120 in terms of conformation enables its binding to a conformationally inert site on CD4 [38]