HIV-1 Gag: An Emerging Target for Antiretroviral Therapy

Tedbury, Philip R.; Freed, Eric O.

doi:10.1007/82_2015_436

Cited by 19 publications

(17 citation statements)

References 176 publications

(238 reference statements)

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“…Overall, HIV-1 CA is poorly tolerant of mutation, with most amino acid changes resulting in a dysfunctional capsid and severely impaired virus infectivity (19,20), limiting the ability of HIV-1 to adapt to capsid-targeting therapies. The combination of its critical function, specific host factor interactions, and mutational fragility makes the capsid a desirable target for antiretroviral intervention (21,22).…”

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confidence: 99%

CA Mutation N57A Has Distinct Strain-Specific HIV-1 Capsid Uncoating and Infectivity Phenotypes

Fischer

Saito

Kline

et al. 2019

J Virol

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The ability of human immunodeficiency virus type 1 (HIV-1) to transduce nondividing cells is key to infecting terminally differentiated macrophages, which can serve as a long-term reservoir of HIV-1 infection. The mutation N57A in the viral CA protein renders HIV-1 cell cycle dependent, allowing examination of HIV-1 infection of nondividing cells. Here, we show that the N57A mutation confers a postentry infectivity defect that significantly differs in magnitude between the common lab-adapted molecular clones HIV-1NL4-3 (>10-fold) and HIV-1LAI (2- to 5-fold) in multiple human cell lines and primary CD4+ T cells. Capsid permeabilization and reverse transcription are altered when N57A is incorporated into HIV-1NL4-3 but not HIV-1LAI. The N57A infectivity defect is significantly exacerbated in both virus strains in the presence of cyclosporine (CsA), indicating that N57A infectivity is dependent upon CA interacting with host factor cyclophilin A (CypA). Adaptation of N57A HIV-1LAI selected for a second CA mutation, G94D, which rescued the N57A infectivity defect in HIV-1LAI but not HIV-1NL4-3. The rescue of N57A by G94D in HIV-1LAI is abrogated by CsA treatment in some cell types, demonstrating that this rescue is CypA dependent. An examination of over 40,000 HIV-1 CA sequences revealed that the four amino acids that differ between HIV-1NL4-3 and HIV-1LAI CA are polymorphic, and the residues at these positions in the two strains are widely prevalent in clinical isolates. Overall, a few polymorphic amino acid differences between two closely related HIV-1 molecular clones affect the phenotype of capsid mutants in different cell types. IMPORTANCE The specific mechanisms by which HIV-1 infects nondividing cells are unclear. A mutation in the HIV-1 capsid protein abolishes the ability of the virus to infect nondividing cells, serving as a tool to examine cell cycle dependence of HIV-1 infection. We have shown that two widely used HIV-1 molecular clones exhibit significantly different N57A infectivity phenotypes due to fewer than a handful of CA amino acid differences and that these clones are both represented in HIV-infected individuals. As such minor differences in closely related HIV-1 strains may impart significant infectivity differences, careful consideration should be given to drawing conclusions from one particular HIV-1 clone. This study highlights the potential for significant variation in results with the use of multiple strains and possible unanticipated effects of natural polymorphisms.

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confidence: 99%

CA Mutation N57A Has Distinct Strain-Specific HIV-1 Capsid Uncoating and Infectivity Phenotypes

Fischer

Saito

Kline

et al. 2019

J Virol

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“…Among viral proteins that are not exploited as an antiviral target, the viral capsid (CA) protein is an attractive target for antiviral interventions (2,3). CA, a genetically fragile protein (4), exhibits limited tolerance to genetic changes and, hence, would predictably temper the evolution of drug resistance (5).…”

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confidence: 99%

Roles of Capsid-Interacting Host Factors in Multimodal Inhibition of HIV-1 by PF74

Saito

Ferhadian

Sowd

et al. 2016

J Virol

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The viral capsid of HIV-1 interacts with a number of host factors to orchestrate uncoating and regulate downstream events, such as reverse transcription, nuclear entry, and integration site targeting. PF-3450074 (PF74), an HIV-1 capsid-targeting low-molecular-weight antiviral compound, directly binds to the capsid (CA) protein at a site also utilized by host cell proteins CPSF6 and NUP153. Here, we found that the dose-response curve of PF74 is triphasic, consisting of a plateau and two inhibitory phases of different slope values, consistent with a bimodal mechanism of drug action. High PF74 concentrations yielded a steep curve with the highest slope value among different classes of known antiretrovirals, suggesting a dose-dependent, cooperative mechanism of action. CA interactions with both CPSF6 and cyclophilin A (CypA) were essential for the unique dose-response curve. A shift of the steep curve at lower drug concentrations upon blocking the CA-CypA interaction suggests a protective role for CypA against high concentrations of PF74. These findings, highlighting the unique characteristics of PF74, provide a model in which its multimodal mechanism of action of both noncooperative and cooperative inhibition by PF74 is regulated by interactions of cellular proteins with incoming viral capsids. IMPORTANCEPF74, a novel capsid-targeting antiviral against HIV-1, shares its binding site in the viral capsid protein (CA) with the host factors CPSF6 and NUP153. This work reveals that the dose-response curve of PF74 consists of two distinct inhibitory phases that are differentially regulated by CA-interacting host proteins. PF74's potency depended on these CA-binding factors at low doses. In contrast, the antiviral activity of high PF74 concentrations was attenuated by cyclophilin A. These observations provide novel insights into both the mechanism of action of PF74 and the roles of host factors during the early steps of HIV-1 infection.T he emergence of HIV-1 variants resistant to currently approved antiretrovirals necessitates the development of novel classes of inhibitors that possess high levels of genetic barriers to resistance (1). Among viral proteins that are not exploited as an antiviral target, the viral capsid (CA) protein is an attractive target for antiviral interventions (2, 3). CA, a genetically fragile protein (4), exhibits limited tolerance to genetic changes and, hence, would predictably temper the evolution of drug resistance (5). The mutational intolerance of CA is caused by structural and functional constraints (6-8). CA, which is the major virion core structural protein, generated by protease-mediated cleavage of the precursor Gag Pr55 protein, plays essential roles during both particle assembly and disassembly (9, 10). Perhaps it is this genetic fragility that makes CA highly vulnerable to host immune responses, such as CD8-specific adaptive immunity (11) and TRIM5␣-mediated intrinsic immunity (12), both of which target highly conserved portions of CA.Recent work discovered several novel smal...

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“…There are multiple drugs known to target the virus capsid during either the early or late stages of the replication cycle, including assembly and maturation inhibitors. 51 Some drugs, such as PF-3450074 (PF74, Figure 2 D), target multiple stages of the viral cycle, and the resulting phenotype of PF74-treated viruses involves aberrant assembly, altered nuclear entry pathways, and prevention of uncoating and reverse transcription. 52 Crystal structures of PF74 bound to monomeric CA, 53 as well as to hexameric CA, 54 − 56 indicate that the drug binds to the capsid within a pocket at the center of the N-terminal domain ( Figure 2 E,F).…”

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All-Atom Molecular Dynamics of Virus Capsids as Drug Targets

Perilla

Hadden

Goh

et al. 2016

J. Phys. Chem. Lett.

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Virus capsids are protein shells that package the viral genome. Although their morphology and biological functions can vary markedly, capsids often play critical roles in regulating viral infection pathways. A detailed knowledge of virus capsids, including their dynamic structure, interactions with cellular factors, and the specific roles that they play in the replication cycle, is imperative for the development of antiviral therapeutics. The following Perspective introduces an emerging area of computational biology that focuses on the dynamics of virus capsids and capsid–protein assemblies, with particular emphasis on the effects of small-molecule drug binding on capsid structure, stability, and allosteric pathways. When performed at chemical detail, molecular dynamics simulations can reveal subtle changes in virus capsids induced by drug molecules a fraction of their size. Here, the current challenges of performing all-atom capsid–drug simulations are discussed, along with an outlook on the applicability of virus capsid simulations to reveal novel drug targets.

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HIV-1 Gag: An Emerging Target for Antiretroviral Therapy

Cited by 19 publications

References 176 publications

CA Mutation N57A Has Distinct Strain-Specific HIV-1 Capsid Uncoating and Infectivity Phenotypes

CA Mutation N57A Has Distinct Strain-Specific HIV-1 Capsid Uncoating and Infectivity Phenotypes

Roles of Capsid-Interacting Host Factors in Multimodal Inhibition of HIV-1 by PF74

All-Atom Molecular Dynamics of Virus Capsids as Drug Targets

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