# Comprehensive Insights into the Molecular Basis of HIV Glycoprotein
## 2 Proteins Engaged in HIV Entry
### gp120  
HIV-1 gp120 is a viral membrane spike glycoprotein composed of three molecules anchored in the viral membrane by the linked gp41 protein. gp120 plays a significant role in mediating the entry of HIV into host cells and triggering the T-cell immune response [84]. In various cell types, including lymphocytes, neurons, and cardiomyocytes, soluble gp120 can induce apoptosis. Studies conducted in rat hippocampal slices, cortical cells, and through in vivo intracerebral injections have confirmed that gp120 induces apoptosis. This apoptotic effect is mediated by gp120 binding to neuronal membrane coreceptors such as CCR3, CCR5, and CXCR4. Additionally, soluble gp120 contributes to the release of arachidate by glial cells, disrupting glutamate reuptake in astrocytes and neurons, prolonging activation of NMDA receptors, and disrupting cellular calcium (Ca\({}^{2+}\)) homeostasis. Consequently, the generation of superoxide and peroxide species in mitochondria is triggered, leading to the activation of caspases and endonucleases, oxidative stress, and mitochondrial permeabilization, ultimately resulting in neuronal cell death [85]. gp120, a globular glycoprotein weighing 120 kDa, is comprised of 480 amino acids with approximately 20-35 N-glycosylation sites, nine disulfide bridges, and five conserved regions (C1-C5) interspersed with five variable regions or loops (V1-V5), (Figures 2a and 4a) [84]. The structure of gp120 folds and generates an outer domain, an inner domain (incorporating the C and N termini associated with gp41), and a bridging sheet that connects these two domains. The CD4 binding pocket is above the bridging sheet and between the outer and inner domains [86]. While the conserved regions constitute the core, the variable regions are positioned near the surface of gp120. Nonetheless, all three domains of gp120 play crucial roles in binding to CD4 and coreceptors. Glycosylation of gp120 predominantly occurs on the protein surface, particularly on the outer domain and the V4 and V5 variable loops, which harbor an immunosilent face [84]. Figure 4: HIV-1 Env gp120 and gp41 Structures. (**a**) Ribbon diagram of gp120 core: The ribbon diagram of the gp120 core displays its \(\alpha\)-helices (\(\alpha\)1-\(\alpha\)5) and \(\beta\)-strands (1–25). The relative positions of the variable loops (V1–V5) and the N- and C-termini are indicated. In this orientation, the viral membrane is positioned at the top and the cell membrane at the bottom. Upon binding to CD4, gp120 forms a bridging sheet composed of four \(\beta\)-strands, which separate the inner and outer domains of gp120 with their orientation in the trimeric complex. (**b**) Ribbon diagram of gp120 core with interaction sites: This diagram shows the gp120 core as in (**a**), highlighting the N-terminus (red) and  
the gp41 interaction site (blue). The inner domain is depicted in red and gray, while the outer domain is shown in orange. The bridging sheet, which includes elements from the inner and outer domains, is illustrated in gray and orange. (**c**) Trimeric gp120 bound to CD4 and antibody Fab: The trimeric gp120 is shown in the same colors as in (**b**), bound to three molecules of CD4 (yellow) and the Fab fragment from the neutralizing antibody 17b (brown), used to stabilize the gp120 structure. This complex is superimposed onto the electron density observed by cryo-electron tomography (light gray). The right side shows the same structure rotated 90\({}^{\circ}\), positioning the viral membrane in the plane of the page. (**d**) Three-dimensional representation of HIV-1 Env in CD4-bound conformation: On the left, a trimeric Env spike (blue) is anchored in the lipid bilayer of the viral membrane (gray). The white arrow indicates the predicted location of gp41. On the right, a ribbon diagram of the gp120 core (red) is superimposed on the density map (blue), with the V1/V2 loop in yellow and the V3 loop in green. Reprinted (adapted) with permission from [31] Copyright Elsevier (2024).