Abstract:
: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.
journal_name
J Viroljournal_title
Journal of virologyauthors
Fischer DK,Saito A,Kline C,Cohen R,Watkins SC,Yamashita M,Ambrose Zdoi
10.1128/JVI.00214-19subject
Has Abstractpub_date
2019-04-17 00:00:00issue
9eissn
0022-538Xissn
1098-5514pii
JVI.00214-19journal_volume
93pub_type
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.64.7.3259-3264.1990
更新日期:1990-07-01 00:00:00
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更新日期:1972-10-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:1979-08-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.68.3.1350-1359.1994
更新日期:1994-03-01 00:00:00
abstract::Marburg virus, a filovirus, causes severe hemorrhagic fever with hitherto poorly understood molecular pathogenesis. We have investigated here the vectorial transport of the surface protein GP of Marburg virus in polarized epithelial cells. To this end, we established an MDCKII cell line that was able to express GP per...
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pub_type: 杂志文章
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更新日期:2001-02-01 00:00:00
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pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.68.8.5300-5305.1994
更新日期:1994-08-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.69.9.5640-5649.1995
更新日期:1995-09-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.15.9786-9798.2005
更新日期:2005-08-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.65.8.4480-4485.1991
更新日期:1991-08-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
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pub_type: 杂志文章
doi:10.1128/JVI.19.2.490-494.1976
更新日期:1976-08-01 00:00:00
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journal_title:Journal of virology
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journal_title:Journal of virology
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.25.1.274-284.1978
更新日期:1978-01-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01413-09
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.69.11.7309-7314.1995
更新日期:1995-11-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:1996-08-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.11.6909-6917.2005
更新日期:2005-06-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:2004-07-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.8.3.257-264.1971
更新日期:1971-09-01 00:00:00