Abstract
The Human Immunodeficiency Virus type 1 (HIV-1) virion contains a conical shell, termed capsid, encasing the viral RNA genome. After cellular entry of the virion, the capsid is released and ensures the protection and delivery of the HIV-1 genome to the host nucleus for integration. The capsid relies on many virus–host factor interactions which are regulated spatiotemporally throughout the course of infection. In this paper, we will review the current understanding of the highly dynamic HIV-1 capsid–host interplay during the early stages of viral replication, namely intracellular capsid trafficking after viral fusion, nuclear import, uncoating, and integration of the viral genome into host chromatin. Conventional anti-retroviral therapies primarily target HIV-1 enzymes. Insights of capsid structure have resulted in a first-in-class, long-acting capsid-targeting inhibitor, GS-6207 (Lenacapavir). This inhibitor binds at the interface between capsid protein subunits, a site known to bind host factors, interferes with capsid nuclear import, HIV particle assembly, and ordered assembly. Our review will highlight capsid structure, the host factors that interact with capsid, and high-throughput screening techniques, specifically genomic and proteomic approaches, that have been and can be used to identify host factors that interact with capsid. Better structural and mechanistic insights into the capsid–host factor interactions will significantly inform the understanding of HIV-1 pathogenesis and the development of capsid-centric antiretroviral therapeutics.
Highlights
Human Immunodeficiency Virus type 1 (HIV-1) is a lentivirus containing two RNA genomes that must be reverse transcribed into double-stranded DNA and integrated into the host genome to ensure a productive infection [1]
Our review will highlight capsid structure, the host factors that interact with capsid, and highthroughput screening techniques, genomic and proteomic approaches, that have been and can be used to identify host factors that interact with capsid
Better structural and mechanistic insights into the capsid–host factor interactions will significantly inform the understanding of HIV-1 pathogenesis and the development of capsid-centric antiretroviral therapeutics
Summary
Human Immunodeficiency Virus type 1 (HIV-1) is a lentivirus containing two RNA genomes that must be reverse transcribed into double-stranded DNA and integrated into the host genome to ensure a productive infection [1]. Viruses 2021, 13, 417 by providing an expansive area for recognition by diverse cellular proteins acting as either pro-viral or anti-viral factors [15,16,17,18] These host factors bind to unique high-order interfaces only present in the assembled capsid lattice, and they have no or low affinity to CA monomers, underscoring the fact that capsid structural integrity is critical for the interplay with host factors [19]. These potent capsid inhibitors have similar scaffolds and share the same capsid binding pocket with the host proteins CPSF6 and Nup153, which both mediate capsid nuclear entry [29] These findings underscore the value of investigating whether additional host factor-binding sites on capsid can be identified and exploited for novel therapeutic interventions. In the last part of this review, we will briefly introduce the genome- and proteome-based approaches that have been and can be used to characterize virus–host interactions in HIV-1 or other viruses and discuss the potential they hold for identifying new capsidinteracting proteins
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