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  • br Introduction The third variable


    Introduction The third variable (V3) loop of the gp120 envelope glycoprotein (Env) on the surface of human immunodeficiency virus type 1 (HIV-1) becomes exposed after the virus binds CD4, the initial receptor; the V3 loop plays an important role in contacting the coreceptor CCR5 or CXCR4 to mediate viral entry (Cashin et al., 2013, Foda et al., 2001, Hartley et al., 2005, Hongjaisee et al., 2017, Huang et al., 2005, Jiang et al., 2010, Moore and Nara, 1991). The sequence of the V3 loop determines Creatinine HIV-1 tropism, dictating the choice of the coreceptor, CCR5 or CXCR4 (Cardozo et al., 2007, Cashin et al., 2013, Conley et al., 1994, Kumar and Raghava, 2013, Scheib et al., 2006, Svicher et al., 2011). The V3 loop is also immunogenic, and neutralizing Creatinine against V3 often dominate immune responses following Env immunization (Jacob et al., 2015, Julien et al., 2013b, Li et al., 2015, Sirois et al., 2007, Stanfield and Wilson, 2005, Totrov et al., 2010, Watkins et al., 2011, Zolla-Pazner, 2005). In addition to its role in HIV-1 entry and immunogenicity, the V3 loop contributes to the non-covalent association of gp120 with the Env trimer, during the assembly of the viral Env spike (Xiang et al., 2010). In primary HIV-1 strains, the length of the V3 loop is extremely constrained by this assembly requirement; even the insertion of a single glycine residue in the V3 stem leads to destabilization of the Env trimer and shedding of gp120 (Xiang et al., 2010). A hydrophobic patch located in the V3 tip region has been shown to be critical for envelope trimer stability in HIV-1 subtype B strains (Xiang et al., 2010). A single-residue change to a hydrophilic or even to a neutral residue in this hydrophobic patch destabilizes the Env trimer and results in an increase of gp120 shedding, a decrease of Env-mediated membrane fusion and a reduction in virus infectivity. In available structural models of the HIV-1 Env trimer (Julien et al., 2013a, Lee et al., 2016, Lyumkis et al., 2013, Pancera et al., 2014), the V3 loop is located at the apex of the trimer along with the gp120 V1 and V2 variable regions. This apical location potentially allows the V3 loop to participate in interprotomer contacts that contribute to Env trimer stability. For example, substitution of hydrophobic residues near the V3 hydrophobic patch raised the melting temperature of soluble gp140 SOSIP.664 Env trimers (de Taeye et al., 2018, de Taeye et al., 2015). It is not known whether the V3 contribution to Env trimer stability is specific for HIV-1 subtype B strains or also applies to other HIV-1 subtypes or evolutionarily related primate lentiviruses (Hirsch et al., 1995, Sharp and Hahn, 2011). Based on sequence alignment of the V3 region, the hydrophobic patch appears to be well conserved in HIV-1, HIV-2 and the simian immunodeficiency viruses (SIVs), implying an important function. However, given the differences between HIV-1 and HIV-2/SIV with respect to the length and composition of the V1/V2 region (Bohl et al., 2013), the structural organization of the Env trimer apex of these virus lineages may differ. Therefore, in this study, we examined the role of the V3 loop hydrophobic patch and V3 loop length in both HIV-1 and HIV-2 species, as well as in nonhuman primate lentiviruses, SIVs. Our results support the hypothesis that the V3 loop plays an important role in the stability of the unliganded HIV-1, HIV-2 and SIV Env trimers in addition to its role in contacting the coreceptor for viral entry in the CD4-bound state of Env.
    Discussion The gp120 V3 loop of primate immunodeficiency virus Envs is typically 35 amino acid residues in length and can be divided into the base, stem and tip (4, 21). The amino acid sequences of the V3 base and tip are more conserved than that of the stem. Mutagenesis studies have implicated the V3 base and tip in contacting the CCR5 or CXCR4 coreceptors: the V3 base contributes to the interaction with the sulfated N-terminus of the coreceptor, whereas the V3 tip interacts with extracellular loop 2 (ECL2) of the coreceptor (Abayev et al., 2015, Arimont et al., 2017, Huang et al., 2007, Kufareva, 2016). Although the amino acid sequences of the V3 stem are less conserved, our previous study demonstrated that insertions of one or two glycine residues in the V3 stem severely compromised the function of Env from Clade B HIV-1 (Xiang et al., 2010). Part of this functional attenuation arises from decreased coreceptor binding, presumably as a result of disruption of the two-point contact of the V3 base and tip with the coreceptor. The V3 loop length also appears to have been constrained by the requirement for gp120 to associate non-covalently with the assembled Env trimer. Insertion of glycine residues in the V3 stem of Envs from Clade B HIV-1 resulted in shedding of gp120 from the Env trimer, suggesting that the V3 loop might contribute to the non-covalent association of gp120 with the pre-triggered Env trimer (Xiang et al., 2010). Further investigation revealed the importance of the hydrophobic patch in the V3 tip in maintaining the stability of the assembled Env trimer (Xiang et al., 2010). The association of gp120 with the Env trimer correlated with the cell-cell fusion activity of panels of Env mutants derived from a given primate immunodeficiency virus.