Nuclear pore heterogeneity influences HIV-1 infection and the antiviral activity of MX2

Kane, Melissa; Rebensburg, Stephanie V; Takata, Matthew A; Zang, Trinity; Yamashita, Masahiro; Kvaratskhelia, Mamuka; Bieniasz, Paul D.

doi:10.7554/elife.35738

Cited by 120 publications

(199 citation statements)

References 117 publications

(220 reference statements)

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“…This suggests that G94D might provide N57A HIV-1 LAI access to an alternative pathway for infecting dividing cells. This idea is not unreasonable, as a similar cell cycle-dependent CA mutant, N57S, which must gain entry to the nucleus during cell division, relies on a particular set of nucleoporins for infection (59).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…An ACE2 lentivirus expression CS(ACE2)IB vector was constructed by inserting a cDNA encoding an unaltered ACE2 (Addgene; 1786) or a catalytically inactive ACE2 mutant (ACE2-H374N&H378N) into the lentivirus expression vector CSIB (Kane et al, 2018). In this vector, expression of the inserted cDNA is driven by a spleen focus-forming virus promoter and is linked to an internal ribosome entry site blasticidin.…”

Section: Plasmid Constructsmentioning

confidence: 99%

Measuring SARS-CoV-2 neutralizing antibody activity using pseudotyped and chimeric viruses

Schmidt

Weisblum

Muecksch

et al. 2020

Journal of Experimental Medicine

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540

445

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The emergence of SARS-CoV-2 and the ensuing explosive epidemic of COVID-19 disease has generated a need for assays to rapidly and conveniently measure the antiviral activity of SARS-CoV-2–specific antibodies. Here, we describe a collection of approaches based on SARS-CoV-2 spike-pseudotyped, single-cycle, replication-defective human immunodeficiency virus type-1 (HIV-1), and vesicular stomatitis virus (VSV), as well as a replication-competent VSV/SARS-CoV-2 chimeric virus. While each surrogate virus exhibited subtle differences in the sensitivity with which neutralizing activity was detected, the neutralizing activity of both convalescent plasma and human monoclonal antibodies measured using each virus correlated quantitatively with neutralizing activity measured using an authentic SARS-CoV-2 neutralization assay. The assays described herein are adaptable to high throughput and are useful tools in the evaluation of serologic immunity conferred by vaccination or prior SARS-CoV-2 infection, as well as the potency of convalescent plasma or human monoclonal antibodies.

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“…An ACE2 lentivirus expression CS(ACE2)IB vector was constructed by inserting a cDNA encoding an unaltered ACE2 (Addgene:1786) or an catalytically inactive ACE2 mutant (ACE2-H374N&H378N) into the lentivirus expression vector CSIB (Kane et al, 2018). In this vector, expression of the inserted cDNA is driven by a an SSFV promoter and is linked to an IRESblasticidin.…”

Section: Plasmid Constructsmentioning

confidence: 99%

Measuring SARS-CoV-2 neutralizing antibody activity using pseudotyped and chimeric viruses

Schmidt

Weisblum

Muecksch

et al. 2020

Preprint

242

446

View full text Add to dashboard Cite

The emergence of SARS-CoV-2 and the ensuing explosive epidemic of COVID19 disease has generated a need for assays to rapidly and conveniently measure the antiviral activity of SARS-CoV-2-specific antibodies. Here, we describe a collection of approaches based on SARS-CoV-2 spike-pseudotyped, single-cycle, replication-defective human immunodeficiency virus type-1 (HIV-1) and vesicular stomatitis virus (VSV), as well as a replication-competent VSV/SARS-CoV-2 chimeric virus. While each surrogate virus exhibited subtle differences in the sensitivity with which neutralizing activity was detected, the neutralizing activity of both convalescent plasma and human monoclonal antibodies measured using each virus correlated quantitatively with neutralizing activity measured using an authentic SARS-CoV-2 neutralization assay. The assays described herein are adaptable to high throughput and are useful tools in the evaluation of serologic immunity conferred by vaccination or prior SARS-CoV-2 infection, as well as the potency of convalescent plasma or human monoclonal antibodies.

show abstract

Nuclear pore heterogeneity influences HIV-1 infection and the antiviral activity of MX2

Cited by 120 publications

References 117 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

Measuring SARS-CoV-2 neutralizing antibody activity using pseudotyped and chimeric viruses

Measuring SARS-CoV-2 neutralizing antibody activity using pseudotyped and chimeric viruses

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