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Structure of HIV-1 capsid. (A) The structure of the CA monomer showing the N-terminal domain (NTD), the C-terminal domain and the CypA-binding loop (highlighted) (PDB 4XFY) [20]. (B) The structure of pentameric HIV-1 CA (PDB 3P05) [21]. (C) The structure of hexameric HIV-1 CA (PDB 4XFY) [20]. (D) The hexameric and pentameric subunits assemble into a fullerene conical capsid core (PDB 3J3Y). In this model, the core is composed of 186 hexamers and 12 pentamers [22].
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In recent years, major advances in research and experimental approaches have significantly increased our knowledge on the role of the HIV-1 capsid in the virus life cycle, from reverse transcription to integration and gene expression. This makes the capsid protein a good pharmacological target to inhibit HIV-1 replication. This review covers our cu...
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The viral capsid plays a key role in HIV-1 reverse transcription. Recent studies have demonstrated that the small molecule IP6 dramatically enhances reverse transcription in vitro by stabilizing the viral capsid. Reverse transcription results in marked changes in the biophysical properties of the capsid, ultimately resulting in its breakage and dis...
Citations
... HIV employs several mechanisms to avoid detection by the innate immune system [140][141][142]. For example, the HIV-1 capsid has been proposed to traffic into the nucleus, where uncoating, reverse transcription and integration takes place, shielding HIV-1 from cytoplasmic sensors [143,144]. Additionally, HIV-1 proviral mRNA transcripts, similar to cellular mRNAs, are modified by post-transcriptional modifications including 5 ′ capping and the addition of a poly-A tail and/or post-transcriptional modification of RNAs such as m6A, evading detection by cell intrinsic innate immune responses [145,146]. In the context of defective viruses, mechanisms mediated by accessory genes such as Vpr, Nef or Vpu to antagonize innate immune pathways would be altered by deletions, mutations, and frameshifts associated with the defective genomes [147][148][149][150][151]. Understanding mechanisms that trigger hyperinflammation, including the role of different HIV-1 RNAs and their sensors, will provide insights into the mechanisms of HIV-mediated inflammation and identify potential therapeutic targets that would improve the quality of life for PWH by relieving comorbidities associated with chronic HIV-1. ...
People with HIV exhibit persistent inflammation that correlates with HIV-associated comorbidities including accelerated aging, increased risk of cardiovascular disease, and neuroinflammation. Mechanisms that perpetuate chronic inflammation in people with HIV undergoing antiretroviral treatments are poorly understood. One hypothesis is that the persistent low-level expression of HIV proviruses, including RNAs generated from defective proviral genomes, drives the immune dysfunction that is responsible for chronic HIV pathogenesis. We explore factors during HIV infection that contribute to the generation of a pool of defective proviruses as well as how HIV-1 mRNA and proteins alter immune function in people living with HIV.
... The HIV-1 capsid protein that forms the capsid shell surrounding the viral genome has emerged as a key element in several early steps of the HIV-1 life cycle, in addition to the well-established assembly and maturation stages (AlBurtamani et al., 2021;Scoca and Di Nunzio, 2021;Muller et al., 2022). The capsid present in the nucleus of infected cells was shown to be a determinant of HIV-1 nuclear import (Yamashita et al., 2007) and affect HIV-1 integration (Dismuke and Aiken, 2006;Vozzolo et al., 2010). ...
... The capsid present in the nucleus of infected cells was shown to be a determinant of HIV-1 nuclear import (Yamashita et al., 2007) and affect HIV-1 integration (Dismuke and Aiken, 2006;Vozzolo et al., 2010). transcription, trafficking, nuclear import, and integration (AlBurtamani et al., 2021;Scoca and Di Nunzio, 2021;Muller et al., 2022). At the same time, several small molecules have been developed that antagonise the binding of host factors to the HIV-1 capsid (AlBurtamani et al., 2021). ...
... transcription, trafficking, nuclear import, and integration (AlBurtamani et al., 2021;Scoca and Di Nunzio, 2021;Muller et al., 2022). At the same time, several small molecules have been developed that antagonise the binding of host factors to the HIV-1 capsid (AlBurtamani et al., 2021). Although most of these molecules have been used as research tools to understand the HIV-1 life cycle, one of them, Lenacapavir, also known with its brand name Sunlenca, was approved in December 2022 by the US Food and Drug Administration (FDA) as a first-in-class long-acting ART (Segal-Maurer et al., 2022). ...
Lenacapavir, targeting the HIV-1 capsid, is the first-in-class antiretroviral drug recently approved for clinical use. The development of Lenacapavir is attributed to the remarkable progress in our understanding of the capsid protein made during the last few years. Considered little more than a component of the virus shell to be shed early during infection, capsid has been found to be a key player in the HIV-1 life cycle by interacting with multiple host cell factors, entering the nucleus, and directing integration. Here, we describe the key advances that led to this “capsid revolution”.
... Lenacapavir is highly potent, with a 50% effective concentration (EC 50 ) of 31-95 pM [6], and is a long-acting compound with a current upkeep dosing at 6-month intervals [7]. Additionally, there are dozens of compounds reported to bind the HIV-1 capsid with over five mechanisms of action that stabilize or destabilize it, as well as some that interfere with host factor interactions [8][9][10]. Since the capsid relies on a highly sensitive network of interactions, the viral capsid protein is great for drug design, but it is challenging to study. ...
... The most agreed-upon mechanism of action for HIV-1 capsid-targeting antiretrovirals is impacting the capsid assembly and thus losing its protective and trafficking roles, as reviewed in AlBurtamani et al. They reviewed the role of CA during the early steps of HIV-1 lifecycle, from entry to integration [9]. This was complemented in a review by Engleman (2021), which outlined the influence of capsid in integration and provided perspective on how capsid-targeting antivirals could modify integration processes as a primary or secondary mechanism of action [16]. ...
Not many structures are common among all viruses: only nucleic acid and a protein coat [...]
... The flexible nature of CA also allows for the interaction of a range of host factors such as CPSF6, NUP153, NUP358, TRIM5α and MxB [61]. One of the more notable host factors that binds to the CA domain of the precursor PR55 Gag is the proline isomerase cyclophilin A (CypA) [62]. An extended proline-rich loop between the fourth and fifth helices in the NTD compose the binding site for CypA [63]. ...
Once merely thought of as the protein responsible for the overall physical nature of the human immunodeficiency virus type 1 (HIV-1), the Gag polyprotein has since been elucidated to have several roles in viral replication and functionality. Over the years, extensive research into the polyproteins’ structure has revealed that Gag can mediate its own trafficking to the plasma membrane, it can interact with several host factors and can even aid in viral genome packaging. Not surprisingly, Gag has also been associated with HIV-1 drug resistance and even treatment failure. Therefore, this review provides an extensive overview of the structural and functional roles of the HIV-1 Gag domains in virion integrity, functionality and infectivity.
... The RK mutation inhibits viral epitope presentation (18,25) but significantly reduces HIV-1 infectivity (12,14,18,21,(24)(25)(26)(27). This is because CA is genetically fragile (28,29) and is a key regulator of HIV-1 replication (30)(31)(32)(33)(34)(35)(36). Particularly, CA forms the capsid shell that houses the viral genome and other viral/cellular factors (37)(38)(39)(40). ...
HIV-1 replication is durably controlled without antiretroviral therapy (ART) in certain infected individuals called elite controllers (ECs). These individuals express specific human leukocyte antigens (HLA) that tag HIV-infected cells for elimination by presenting viral epitopes to CD8+ cytotoxic T-lymphocytes (CTL). In HIV-infected individuals expressing HLA-B27, CTLs primarily target the viral capsid protein (CA)-derived KK10 epitope. While selection of CA mutation R264K helps HIV-1 escape this potent CTL response, the accompanying fitness cost severely diminishes virus infectivity. Interestingly, selection of a compensatory CA mutation S173A restores HIV-1 replication. However, the molecular mechanism(s) underlying HIV-1 escape from this ART-free virus control by CTLs is not fully understood. Here, we report that the R264K mutation-associated infectivity defect arises primarily from impaired HIV-1 DNA integration, which is restored by the S173A mutation. Unexpectedly, the integration defect of the R264K variant was also restored upon depletion of the host cyclophilin A. These findings reveal a nuclear crosstalk between CA and HIV-1 integration as well as identify a previously unknown role of cyclophilin A in viral DNA integration. Finally, our study identifies a novel immune escape mechanism of an HIV-1 variant escaping a CA-directed CTL response.
... 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][10][11][12][13][14]. These functions are fundamental to HIV-1 biology and therefore there is high interest in developing drugs that perturb capsid functions [15,16]. ...
The capsid core of HIV-1 is a large macromolecular assembly that surrounds the viral genome and is an essential component of the infectious virus. In addition to its multiple roles throughout the viral life cycle, the capsid interacts with multiple host factors. Owing to its indispensable nature, the HIV-1 capsid has been the target of numerous antiretrovirals, though most capsid-targeting molecules have not had clinical success until recently. Lenacapavir, a long-acting drug that targets the HIV-1 capsid, is currently undergoing phase 2/3 clinical trials, making it the most successful capsid inhibitor to-date. In this review, we detail the role of the HIV-1 capsid protein in the virus life cycle, categorize antiviral compounds based on their targeting of five sites within the HIV-1 capsid, and discuss their molecular interactions and mechanisms of action. The diverse range of inhibition mechanisms provides insight into possible new strategies for designing novel HIV-1 drugs and furthers our understanding of HIV-1 biology.
Graphical Abstract
The HIV-1 capsid protein (CA) assumes distinct assembly forms during replication, each presenting unique, solvent-accessible surfaces that facilitate multifaceted functions and host factor interactions. However, contributions of individual CA assemblies remain unclear, as the evaluation of CA in cells presents several technical challenges. To address this need, we sought to identify CA assembly form-specific aptamers. Aptamer subsets with different specificities emerged from within a highly converged, pre-enriched aptamer library previously selected to bind the CA hexamer lattice. Subsets were either highly specific for CA lattice or bound both CA lattice and CA hexamer. We further evaluated four representatives to reveal aptamer structural features required for binding, highlighting interesting features and challenges in aptamer structure determination. Importantly, our aptamers bind biologically relevant forms of CA and we demonstrate aptamer-mediated affinity purification of CA from cell lysates without virus or host modification. Thus, we have identified CA assembly form-specific aptamers that represent exciting new tools for the study of CA.
The human immunodeficiency virus type 1 (HIV-1) genome encodes 15 proteins that perform structural, enzymatic, regulatory, and accessory functions. The capsid protein (CA) is the primary structural protein of HIV-1 and plays multiple functions during infection. Early studies predicted that HIV-1 CA mainly protected and delivered the viral genome to the target cell. However, it is now well established that CA plays a critical role after the cellular entry steps of infection. During the early stages, CA promotes reverse transcription of the RNA genome into a DNA copy and the nuclear import/entry step of HIV-1 infection. Emerging evidence also supports the functional role of CA in the post-nuclear entry steps of infection, such as HIV-1 integration. During the late stages of infection, CA coordinates hexameric lattice formation for the assembly of immature virion. CA also regulates theformation of the mature capsid that encases the viral genome and associated factors in the infectious progeny virion. Because of these indispensable roles, HIV-1 CA has emerged as a new and validated target for antiviral drug development. Accordingly, the first CA-targeting drug, lenacapavir (GS-6207), was recently approved to treat certain HIV-1-infected individuals whose viral load cannot be controlled by other antiviral drugs. Still, new and superior CA inhibitors are needed to qualify as part of the front-line antiviral therapy regimens for all infected individuals. The development of such inhibitors requires a clear understanding of CA’s role in HIV-1 infection. In this review, we will describe CA’s role during the early stages of HIV-1 infection, with particular emphasis on post-nuclear entry steps.
IMPORTANCE
HIV-1 capsid protein (CA)—independently or by recruiting host factors—mediates several key steps of virus replication in the cytoplasm and nucleus of the target cell. Research in the recent years have established that CA is multifunctional and genetically fragile of all the HIV-1 proteins. Accordingly, CA has emerged as a validated and high priority therapeutic target, and the first CA-targeting antiviral drug was recently approved for treating multi-drug resistant HIV-1 infection. However, development of next generation CA inhibitors depends on a better understanding of CA’s known roles, as well as probing of CA’s novel roles, in HIV-1 replication. In this timely review, we present an updated overview of the current state of our understanding of CA’s multifunctional role in HIV-1 replication—with a special emphasis on CA’s newfound post-nuclear roles, highlight the pressing knowledge gaps, and discuss directions for future research.
The HIV-1 capsid, composed of approximately 1,200 copies of the capsid protein, encases genomic RNA alongside viral nucleocapsid, reverse transcriptase, and integrase proteins. After cell entry, the capsid interacts with a myriad of host factors to traverse the cell cytoplasm, pass through the nuclear pore complex (NPC), and then traffic to chromosomal sites for viral DNA integration. Integration may very well require the dissolution of the capsid, but where and when this uncoating event occurs remains hotly debated. Based on size constraints, a long-prevailing view was that uncoating preceded nuclear transport, but recent research has indicated that the capsid may remain largely intact during nuclear import, with perhaps some structural remodeling required for NPC traversal. Completion of reverse transcription in the nucleus may further aid capsid uncoating. One canonical type of host factor, typified by CPSF6, leverages a Phe-Gly (FG) motif to bind capsid. Recent research has shown these peptides reside amid prion-like domains (PrLDs), which are stretches of protein sequence devoid of charged residues. Intermolecular PrLD interactions along the exterior of the capsid shell impart avid host factor binding for productive HIV-1 infection. Herein we overview capsid–host interactions implicated in HIV-1 ingress and discuss important research questions moving forward. Highlighting clinical relevance, the long-acting ultrapotent inhibitor lenacapavir, which engages the same capsid binding pocket as FG host factors, was recently approved to treat people living with HIV.
