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Cellular proteins interacting with curved HIV-1 capsid lattices

ABSTRACT: Early events of HIV-1 lifecycle, such as post-entry virus trafficking, uncoating and nuclear import, remain poorly understood due to limited information about virus-host interactions. We used a multidisciplinary approach. First, a mass spectrometry (MS)-based proteomics methodology enabled us to identify cellular proteins that specifically bind to 3-dimensional curved hexameric capsid lattices closely mimicking the assembled HIV-1 core. We then employed virology, live cell imaging, CRISPR gene knockout, x-ray crystallography, and biochemistry to demonstrate that Sec24C (a component of the COPII complex) is the first example of a cytoplasmic protein that utilizes an FG containing motif to directly and specifically bind the curved hexameric HIV-1 capsid lattices.

INSTRUMENT(S): LTQ Orbitrap XL, Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Monocyte, Cell Culture

SUBMITTER: Nikoloz Shkriabai

LAB HEAD: Mamuka Kvaratskhelia

PROVIDER: PXD020970 | Pride | 2021-01-04

REPOSITORIES: Pride

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Project description:Macrophages provide an interface between innate and adaptive immunity and are important long-lived reservoirs for Human Immunodeficiency Virus Type-1 (HIV-1). Multiple genetic networks involved in regulating signal transduction cascades and immune responses in macrophages are coordinately modulated by HIV-1 infection. To evaluate complex interrelated processes and to assemble an integrated view of activated signaling networks, a systems biology strategy was applied to genomic and proteomic responses by primary human macrophages over the course of HIV-1 infection. Macrophage responses, including cell cycle, calcium, apoptosis, mitogen-activated protein kinases (MAPK), and cytokines/chemokines, to HIV-1 were temporally regulated, in the absence of cell proliferation. In contrast, Toll-like receptor (TLR) pathways remained unaltered by HIV-1, although TLRs 3, 4, 7, and 8 were expressed and responded to ligand stimulation in macrophages. HIV-1 failed to activate phosphorylation of IRAK-1 or IRF-3, modulate intracellular protein levels of Mx1, an interferon-stimulated gene, or stimulate secretion of TNF, IL-1b, or IL-6. Activation of pathways other than TLR was inadequate to stimulate, via cross-talk mechanisms through molecular hubs, the production of proinflammatory cytokines typical of a TLR response. HIV-1 sensitized macrophage responses to TLR ligands, and the magnitude of viral priming was related to virus replication. HIV-1 induced a primed, proinflammatory state, M1HIV, which increased the responsiveness of macrophages to TLR ligands. HIV-1 might passively evade pattern recognition, actively inhibit or suppress recognition and signaling, or require dynamic interactions between macrophages and other cells, such as lymphocytes or endothelial cells. HIV-1 evasion of TLR recognition and simultaneous priming of macrophages may represent a strategy for viral survival, contribute to immune pathogenesis, and provide important targets for therapeutic approaches. Affymetrix arrays were used to identify genomic macrophage response to HIV during viral spread in culture. Experiment Overall Design: An HIV-1 spreading infection was established in primary human macrophages. RNA was extracted from both viral- and mock-infected macrophages cultures over 7 days and hybridized to Affymetrix HG-U95Av2 GeneChips for analysis.

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Cellular proteins interacting with curved HIV-1 capsid lattices

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