Structure of native HIV-1 cores and their interactions with IP6 and CypA

Ni, Tao; Zhu, Yanhua; Yang, Zhengyi; Xu, Chaoyi; Chaban, Yuriy; Nesterova, Tanya; Ning, Jiying; Böcking, Till; Parker, Michael W.; Monnie, Christina; Ahn, Jin-Woo; Perilla, Juan R.; Zhang, Peijun

doi:10.1126/sciadv.abj5715

Cited by 31 publications

(37 citation statements)

References 73 publications

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“…Imaging of single virus particles immobilized on poly-L-lysine treated glass revealed that, as expected, virions that contained G89V CA alone failed to efficiently incorporate CDR and showed marginal CDR colocalization (~2.5%) with the INmNG labeled cores. In contrast, mixed G89V/K203A CA virions efficiently incorporated CDR, showing 74 [49], we propose that as much as ~2% of virus incorporated CA is packaged in vRNPs.…”

Section: A Fraction Of Unlabeled Ca and Cdr Gets Packaged With Vrnpsmentioning

confidence: 70%

Localization and functions of native and eGFP-tagged capsid proteins in HIV-1 particles

et al. 2022

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In infectious HIV-1 particles, the capsid protein (CA) forms a cone-shaped shell called the capsid, which encases the viral ribonucleoprotein complex (vRNP). Following cellular entry, the capsid is disassembled through a poorly understood process referred to as uncoating, which is required to release the reverse transcribed HIV-1 genome for integration into host chromatin. Whereas single virus imaging using indirect CA labeling techniques suggested uncoating to occur in the cytoplasm or at the nuclear pore, a recent study using eGFP-tagged CA reported uncoating in the nucleus. To delineate the HIV-1 uncoating site, we investigated the mechanism of eGFP-tagged CA incorporation into capsids and the utility of this fluorescent marker for visualizing HIV-1 uncoating. We find that virion incorporated eGFP-tagged CA is effectively excluded from the capsid shell, and that a subset of the tagged CA is vRNP associated. These results thus imply that eGFP-tagged CA is not a direct marker for capsid uncoating. We further show that native CA co-immunoprecipitates with vRNP components, providing a basis for retention of eGFP-tagged and untagged CA by sub-viral complexes in the nucleus. Moreover, we find that functional viral replication complexes become accessible to integrase-interacting host factors at the nuclear pore, leading to inhibition of infection and demonstrating capsid permeabilization prior to nuclear import. Finally, we find that HIV-1 cores containing a mixture of wild-type and mutant CA interact differently with cytoplasmic versus nuclear pools of the CA-binding host cofactor CPSF6. Our results suggest that capsid remodeling (including a loss of capsid integrity) is the predominant pathway for HIV-1 nuclear entry and provide new insights into the mechanism of CA retention in the nucleus via interaction with vRNP components.

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Section: A Fraction Of Unlabeled Ca and Cdr Gets Packaged With Vrnpsmentioning

confidence: 70%

Localization and functions of native and eGFP-tagged capsid proteins in HIV-1 particles

et al. 2022

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“…IP6 beads are shown as orange vdW spheres. [40, 39]. d,e Performance benchmarks with NAMD3 [38], simulating the HIV-1 conical capsid shown in panels c and d. Benchmarks were performed with one CPU per GPU employed.…”

Section: Resultsmentioning

confidence: 99%

“…After applying our framework to HIV-1 CA (Figure 1a), we assembled the full-scale conical capsid bound to the charged assembly co-factor inositol hexakisphosphate [39, 40] (Figure 1b,c, Figure S3). The complete SBCG system of the conical capsid is described by 340,000 beads, representing a larger than 200-fold reduction in particles compared to the atomistic conical capsid of the same morphology.…”

Section: Resultsmentioning

confidence: 99%

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Performance efficient macromolecular mechanics via sub-nanometer shape based coarse graining

Bryer

Perilla

2022

Preprint

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Dimensionality reduction via coarse grain modeling has positioned itself as an indispensable tool for decades, particularly for biomolecular simulations where atomic systems encompass hundreds of millions of atoms. While distinct flavors of coarse grain modeling exist, those occupying the coarse end of the spectrum are typically knowledge based, relying on a priori information to parameterize models, thus hindering general predictive capability. Here, we present an algorithmic and transferable approach known as shape based coarse graining (SBCG) which employs unsupervised machine learning via competitive Hebbian adaptation to construct coarse molecules that perfectly represent atomistic topologies. We show how SBCG provides ample control over model granularity, and we provide a quantitative metric for selection thereof. Parameter optimization, inclusion of small molecule species, as well as simulation configuration are discussed in detail. Our method and its implementation is made available as part of the CGBuilder plugin, present in the widely-used visual molecular dynamics (VMD) and nanoscale molecular dynamics (NAMD) software suites. We demonstrate applications of our method with a variety of systems from the inositol hexaphosphate bound, full-scale HIV-1 capsid to heteromultimeric cofilin-2-bound actin filaments. Overall, we show that SBCG provides a simple yet robust approach to coarse graining that requires minimal user input and lacks any ad hoc interactions between protein domains. Furthermore, because the Hamiltonian employed in SBCG is CHARMM compatible, SBCG takes full advantage of the latest GPU accelerated NAMD3 yielding molecular sampling of over a microsecond per day for systems that span micrometers.

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“…The retroviral Gag lattice is the most prominent feature in both mature and immature particles, and the complex arrangement of these lattices is dictated by intermolecular protein interactions located primarily within the CA domain (79)(80)(81). While the structural determinants of HIV-1 Gag oligomerization have been extensively studied in authentic particles (114)(115)(116), virus-like particles (117)(118)(119), and in vitro assemblies of purified CA proteins (120), high resolution of the structure of the HTLV-1 has been limited to nuclear magnetic resonance (NMR) studies of the HTLV-1 CA domain (121). Comparative studies probing residues within CA have identified many of the key interaction interfaces required for maintaining replication and morphology of HIV-1 (122,123), HIV-2 (124), and HTLV-1 (81), including those that dictate the formation of structural features such as the six-helix bundle of CA-SP1 and the two-and three-fold CA interfaces.…”

Section: Morphological Diversity In Human Retrovirus Particlesmentioning

confidence: 99%

Molecular Biology and Diversification of Human Retroviruses

Meissner

Talledge²,

Mansky³

2022

Front.Virol.

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Studies of retroviruses have led to many extraordinary discoveries that have advanced our understanding of not only human diseases, but also molecular biology as a whole. The most recognizable human retrovirus, human immunodeficiency virus type 1 (HIV-1), is the causative agent of the global AIDS epidemic and has been extensively studied. Other human retroviruses, such as human immunodeficiency virus type 2 (HIV-2) and human T-cell leukemia virus type 1 (HTLV-1), have received less attention, and many of the assumptions about the replication and biology of these viruses are based on knowledge of HIV-1. Existing comparative studies on human retroviruses, however, have revealed that key differences between these viruses exist that affect evolution, diversification, and potentially pathogenicity. In this review, we examine current insights on disparities in the replication of pathogenic human retroviruses, with a particular focus on the determinants of structural and genetic diversity amongst HIVs and HTLV.

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Structure of native HIV-1 cores and their interactions with IP6 and CypA

Abstract: High-resolution cryoET structures of native HIV-1 capsid in complex with IP6 and CypA are enabled by viral membrane perforation.

Cited by 31 publications

References 73 publications

Localization and functions of native and eGFP-tagged capsid proteins in HIV-1 particles

Localization and functions of native and eGFP-tagged capsid proteins in HIV-1 particles

Performance efficient macromolecular mechanics via sub-nanometer shape based coarse graining

Molecular Biology and Diversification of Human Retroviruses

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