Lineage-Specific Differences between Human and Simian Immunodeficiency Virus Regulation of gp120 Trimer Association and CD4 Binding

Abstract

Metastable conformations of the gp120 and gp41 envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) must be maintained in the unliganded state of the envelope glycoprotein trimer. Binding of gp120 to the primary receptor, CD4, triggers the transition to an open conformation of the trimer, promoting interaction with the CCR5 chemokine receptor and ultimately leading to gp41-mediated virus-cell membrane fusion and entry. Topological layers in the gp120 inner domain contribute to gp120-trimer association in the unliganded state and to CD4 binding. Here we describe similarities and differences between HIV-1 and SIVmac gp120. In both viruses, the gp120 N/C termini and the inner domain β-sandwich and layer 2 support the noncovalent association of gp120 with the envelope glycoprotein trimer. Layer 1 of the SIVmac gp120 inner domain contributes more to trimer association than the corresponding region of HIV-1 gp120. On the other hand, layer 1 plays an important role in stabilizing the CD4-bound conformation of HIV-1 but not SIVmac gp120 and thus contributes to HIV-1 binding to CD4. In SIVmac, CD4 binding is instead enhanced by tryptophan 375, which fills the Phe 43 cavity of gp120. Activation of SIVmac by soluble CD4 is dependent on tryptophan 375 and on layer 1 residues that determine a tight association of gp120 with the trimer. Distinct biological requirements for CD4 usage have resulted in lineage-specific differences in the HIV-1 and SIV gp120 structures that modulate trimer association and CD4 binding.

Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope

“…Optimization of SIVsm Env immunogens to preferentially expose certain targets and interact with germ line B-cell receptors may be necessary to elicit a broader antibody profile, as has been suggested for HIV-1 Envs. Despite similarities between SIVsm and HIV-1 Envs, there are also important differences that could affect their immunogenicity, antigenicity, and mucosal transmissibility, particularly differences involving interactions with CD4 (73,119,123,(133)(134)(135)(136)(137)(138)(139)(140)(141). These findings highlight our limited understanding of how well SIVsm Env immunogens, challenge viruses, and neutralization panels model features of HIV-1 Envs that are desirable for vaccines and underscore the need to identify and characterize broadly neutralizing antibodies against SIVsm if this immunization model is going to continue to be pursued.…”

Lineage-Specific Differences between the gp120 Inner Domain Layer 3 of Human Immunodeficiency Virus and That of Simian Immunodeficiency Virus

“…The major contributions of the gp120 N and C termini, the inner domain (the ␤-sandwich, layer 1, layer 2, and layer 3) and the Phe 43 cavity to gp120-trimer association and/or CD4 binding are shown. Note that the contribution of the filled SIVmac239 gp120 Phe 43 cavity to CD4 binding is lacking in HIV-1 gp120; this lack is compensated by a contribution of the HIV-1 gp120 inner domain layer 1 to CD4 binding, as reported previously (17). While layer 3 is important for securing CD4 binding both in HIV-1 (16) and SIV gp120, the contribution appears to be more important in SIVmac239 gp120 due to the contribution of layer 3 to maintain the integrity of the Phe 43 cavity.…”

“…Layers 1 and 2 of the gp120 inner domain were recently shown to be important in maintaining the association of gp120 with the Env trimer in HIV but also SIV lineages (15,17). In HIV-1, layer 3 was also shown to contribute to the association of gp120 with the unliganded Env trimer, likely through an indirect mechanism (16).…”

“…While HIV-1 layers 1 and 2 are required to keep CD4 in place by decreasing the off-rate of the gp120-CD4 interaction (15), layer 3 is implicated in the initial contact and modulates the on-rate of this association (16). Interestingly, lineage-specific differences in the role of layers 1 and 2 regarding their contribution to gp120-trimer association and CD4 binding were recently described (17). Relative to layer 1 of HIV-1 gp120, the SIVmac239 gp120 layer 1 plays a more prominent role in maintaining gp120-trimer association and is minimally involved in promoting CD4 binding (17).…”

“…Interestingly, lineage-specific differences in the role of layers 1 and 2 regarding their contribution to gp120-trimer association and CD4 binding were recently described (17). Relative to layer 1 of HIV-1 gp120, the SIVmac239 gp120 layer 1 plays a more prominent role in maintaining gp120-trimer association and is minimally involved in promoting CD4 binding (17). HIV-2/SIVsmm gp120 glycoproteins, like those of most monkey SIVs, typically have a tryptophan residue at position 375 (18).…”