# Comprehensive Insights into the Molecular Basis of HIV Glycoprotein
## 4 gp41 Env-Matrix  
The HIV-1 matrix in Gag precursors (matrix\({}^{\text{Gag}}\)) physically interacts with gp41 Env [79; 147; 151; 152; 153], a relationship crucial in several viral processes. This interaction enhances Env packaging during viral budding and facilitates the rearrangement of Env pre-bundle structures during viral entry [154; 155; 156]. The gp41 Env-matrix\({}^{\text{Gag}}\) interaction performs multiple functions, including the interaction of gp41 CT with unprocessed Gag in immature HIV-1 particles, suppressing HIV-1 entry [157]. A study used cryo-ET to analyze the Env protein and matrix in HIV-1 particles, achieving a 9.1 A resolution. It revealed unexpected features, such as a variable central core in gp41, diverse glycosylation, and a flexible stalk that affects Env tilting and epitope exposure. In immature particles, Env positioning differed from its placement in mature particles, highlighting the key role of Gag-Env interactions in virus assembly. However, this study used viruses with a truncated Env CT, which is important for interacting with the matrix [32]. Therefore, the exact accommodation of functional Env into the matrix lattice remains to be determined, although some studies have suggested models for this interaction. These findings and future studies elucidating the Env-matrix interface enhance our understanding of HIV assembly and are crucial for developing vaccines and therapies [30; 158]. Upon cleavage of Gag and GagPol precursors by HIV-1 protease, these immature particles transition into mature HIV-1 particles [157]. The proteolytic cleavage of the Gag polyprotein during HIV-1 maturation leads to a reorganization of the matrix lattice, which is crucial for viral entry. This process is dependent on the differential localization of Env glycoprotein trimers, mediated by the interaction between the gp41 Env-matrix\({}^{\text{Gag}}\) interaction [159; 160]. Additionally, this interaction prevents the biotinylation of gp41 CT by matrix\({}^{\text{Gag}}\)[161]. The interaction domains between the basic and C-terminal regions of HIV-1 matrix\({}^{\text{Gag}}\) and gp41 CT involve a physical interaction [152; 162; 163]. The matrix substitution L49D in gp120-gp41 can destabilize this interaction, but the Y710S substitution in gp41 CT can reverse this destabilization [164]. The gp41 Env-matrix\({}^{\text{Gag}}\) interaction relies explicitly on the last 13 to 43 amino acids in the gp41 CT region [165]. Furthermore, mutations in gp41 CT can contribute to resistance against HIV protease inhibitors (PIs) [166]. The HIV-1 Tat protein significantly interacts with Env, playing a key role in viral entry and pathogenesis. Tat's binding to gp120 promotes its conformational change and enhancesviral entry efficiency by facilitating binding to CD4 and coreceptors [147; 167; 168; 169; 170; 171]. Tat forms a complex with native trimeric Env glycoproteins on HIV-1 virions, enhancing the virus's ability to enter dendritic cells via an integrin-mediated endocytic pathway, distinct from the canonical C-type lectin receptor pathway. This interaction, primarily involving the V3 loop of Env, is crucial for viral entry, with modifications to this loop affecting the Tat/Env complex's stability. Shortening Env's V1/V2 loop also enhances this stability, commonly seen in founder viruses at mucosal entry points [172; 173]. Physical interaction between HIV-1 Tat and gp120 has been observed using techniques, including isothermal titration calorimetry, electron cryomicroscopy, ELISA, pulldown assays, and surface plasmon resonance analyses [167; 174; 175; 176]. Extracellular Tat also interacts with chemokine receptors such as CCR2 and CCR3, recruiting chemokine receptor-expressing macrophages and monocytes to HIV-infected cells [176]. Additionally, Tat released from infected cells can physically interact with the extracellular membranes of uninfected cells [167]. The gp120-Tat interaction can alter viral coreceptor tropism, allowing X4-tropic virus gp120 to interact efficiently with CXCR4 and CCR5 [170; 177].