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  • The results of our study indicate

    2021-09-27

    The results of our study indicate the general importance of the gp120 V3 loop A939572 patch in the subunit association of primate immunodeficiency virus Env trimers. Our observation that the stem insertion mutants and hydrophobic patch mutants exhibit similar phenotypes with respect to gp120 shedding implies that precise spatial interactions of the hydrophobic patch are required for Env trimer stability. On the available high-resolution structures of HIV-1 Env trimers (Julien et al., 2013a, Lee et al., 2016, Lyumkis et al., 2013, Pancera et al., 2014), the gp120 V1, V2 and V3 elements are located at the trimer apex (Fig. 7A). In these structures, the V3 hydrophobic patch forms a hydrophobic core by a key-in-hole interaction with the V2 region (F159, M161, and V172) of the same gp120 subunit (Fig. 7B and C). Alteration of the V3 and V2 hydrophobic interactions might destabilize structures near the Env trimer apex that contribute to maintenance of the pre-triggered conformation of the assembled trimer. The structural models suggest that the V2 turn (residues 164–168) immediately adjacent to the V3-V2 hydrophobic core is involved in interprotomer interactions in the Env trimer. An indirect disruption of these V2-mediated interprotomer interactions by alteration of the V3 hydrophobic patch might explain an “opening” of the trimer apex; such HIV-1 mutants would be expected to maintain trimer integrity and replication competence but exhibit increased neutralization sensitivity (Herschhorn et al., 2016). The observed shedding of gp120 resulting from the introduced V3 changes is more difficult to explain, as the gp120 subunits exhibit numerous interactions with gp41 in current Env trimer models (Julien et al., 2013a, Lee et al., 2016, Lyumkis et al., 2013, Pancera et al., 2014). That the gp120 shedding phenotypes of the V3 mutants result from indirect V2-mediated effects seems unlikely when the direct alteration of V2 residues 164–168 did not yield gp120 shedding phenotypes; in fact, most of these V2 mutants exhibited phenotypes similar to those of the wild-type virus (Herschhorn et al., 2016, Madani et al., 2017). Conformational differences between the high-resolution Env trimer structures and that of the pre-triggered Env on virions have been suggested (Alsahafi et al., 2015, Castillo-Menendez et al., 2018, Pancera et al., 2017). Therefore, in the pre-triggered virion Env trimer, the residues in the V3 hydrophobic patch may contribute to Env trimer stability through interactions not evident in current high-resolution structures. Additional structural information on the conformations sampled by the pre-triggered HIV-1 Env trimer may shed light on the mechanism whereby the V3 loop contributes to trimer stability. CD4 binding repositions the V3 loop from a relatively buried location to an extended structure that can interact with the CCR5 or CXCR4 chemokine receptors (Fig. 8). Coreceptor-binding sites in the V3 tip and base are made available for interaction with the chemokine receptor ECL2 and N-terminus, respectively. In this CD4-bound conformation, the distance (Z) between the V3 base and tip may be constrained by the distance between the N-terminal and ECL2 contacts on the chemokine receptor. In a previous report (Xiang et al., 2010), we found that the decreased syncytium-forming ability of some glycine-insertion V3 mutants could be partially compensated by a CCR5 mutant with an N-terminus extended by two glycine residues. The hydrophobic patch contributes to the interaction of the V3 tip with the chemokine receptor ECL2. Changing the hydrophobic patch residues in HIV-1 gp120 to alanine allowed partial CCR5 binding, but substitution of polar (serine) or charged (glutamic acid) residues abolished detectable CCR5 interaction. These results imply that hydrophobic contacts may be required for the efficient interaction of the V3 tip and ECL2 of the chemokine receptor. Differences in the amount of shed gp120 and in the utilization of monkey versus human receptors complicate quantitative comparisons of the relative contribution of the V3 hydrophobic patch to HIV-1/SIV and HIV-1 coreceptor interaction. However, from previous data derived with HIV-1 (Xiang et al., 2010), we expect that glycine insertions and reduction of hydrophobicity in the hydrophobic patch of the HIV-2/SIV gp120 V3 region will significantly decrease CCR5 binding.