Visualizing HIV-1 Capsid and Its Interactions with Antivirals and Host Factors

Abstract

Understanding of the construction and function of the HIV capsid has advanced considerably in the last decade. This is due in large part to the development of more sophisticated structural techniques, particularly cryo-electron microscopy (cryoEM) and cryo-electron tomography (cryoET). The capsid is known to be a pleomorphic fullerene cone comprised of capsid protein monomers arranged into 200–250 hexamers and 12 pentamers. The latter of these induce high curvature necessary to close the cone at both ends. CryoEM/cryoET, NMR, and X-ray crystallography have collectively described these interactions to atomic or near-atomic resolutions. Further, these techniques have helped to clarify the role the HIV capsid plays in several parts of the viral life cycle, from reverse transcription to nuclear entry and integration into the host chromosome. This includes visualizing the capsid bound to host factors. Multiple proteins have been shown to interact with the capsid. Cyclophilin A, nucleoporins, and CPSF6 promote viral infectivity, while MxB and Trim5α diminish the viral infectivity. Finally, structural insights into the intra- and intermolecular interactions that govern capsid function have enabled development of small molecules, peptides, and truncated proteins to disrupt or stabilize the capsid to inhibit HIV replication. The most promising of these, GS6207, is now in clinical trial.

Rotten to the core: antivirals targeting the HIV-1 capsid core

“…HIV-1 is a lentivirus that infects CD4 + human immune cells, such as T cells and macrophages, and is the causative agent of acquired immune deficiency syndrome (AIDS) [ 2 – 4 ]. The biological structure of the infectious HIV-1 particle, also known as the mature virion, has a viral envelope surrounding a “fullerene cone”-shaped capsid shell that encapsulates two copies of the positive-strand RNA genome along with associated cellular factors and viral proteins [ 4 – 9 ]. The capsid core is composed of capsid proteins (CA), also known as p24, that form pentameric and hexameric subunits, which assemble into the mature viral capsid.…”

“…In this review we will refer to the capsid protein as “CA” and to the assembled viral conical core as “capsid” or “core”. Further, capsid serves critical roles in many aspects of the HIV-1 replication cycle such as reverse transcription, cytoplasmic transport, nuclear entry, and virion maturation in addition to interacting with over 20 host factors essential for infection [ 9 – 14 ]. These functions are fundamental to HIV-1 biology and therefore there is high interest in developing drugs that perturb capsid functions [ 15 , 16 ].…”

“…Although these proteins bind CA at different sites, both CypA and CPSF6 have been shown to increase viral fitness and impact the location of integration events [ 34 , 49 – 56 ]. This example is a limited view into the many complex roles of cellular factors for infection (recently reviewed in [ 7 , 9 , 57 ]).…”

HIV Capsid Protein Genetic Diversity Across HIV-1 Variants and Impact on New Capsid-Inhibitor Lenacapavir

“…RT requires intact rings or capsid lattice sections with certain stability and geometry to produce double-stranded DNA genomes that are extruded from the ruptured capsid walls ( Christensen et al, 2020 ) while promoting HIV-1 uncoating ( Aiken and Rousso, 2021 ). Moreover, the capsid interacts with multiple host factors that can either promote or prevent virus infection ( Stremlau et al, 2006 ; Fricke et al, 2014 ; Yamashita and Engelman, 2017 ; Novikova et al, 2019 ; Temple et al, 2020 ; Toccafondi et al, 2021 ; Wilbourne and Zhang, 2021 ).…”

Exposing the invader

“…For example, the restriction factor myxovirus resistance protein B (MxB) is activated by interferons, and has been shown to inhibit the replication of a broad range of viruses, including HIV and herpesviruses ( Liu et al, 2013 ; Matreyek et al, 2014 ; Crameri et al, 2018 ; Schilling et al, 2018 ). However, its mechanism of action is poorly understood ( Wilbourne and Zhang, 2021 ; Xie et al, 2021 ). Now, in eLife, Beate Sodeik and colleagues – including Manutea Serrero from Hanover Medical School as first author – report new insights into the interactions between MxB and herpesviruses ( Serrero et al, 2022 ).…”