A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells

Nature ◽  
1993 ◽  
Vol 365 (6447) ◽  
pp. 666-669 ◽  
Author(s):  
Michael I. Bukrinsky ◽  
Sheryl Haggerty ◽  
Michael P. Dempsey ◽  
Natalia Sharova ◽  
Alexei Adzhubei ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Nuclear Localization Signal ◽  
Matrix Protein ◽  
Dividing Cells ◽  
Localization Signal ◽  
Hiv 1

scholarly journals Oxadiazols: a New Class of Rationally Designed Anti-Human Immunodeficiency Virus Compounds Targeting the Nuclear Localization Signal of the Viral Matrix Protein

2005 ◽  
Vol 79 (20) ◽  
pp. 13028-13036 ◽  
Author(s):  
Omar Haffar ◽  
Larisa Dubrovsky ◽  
Richard Lowe ◽  
Reem Berro ◽  
Fatah Kashanchi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Nuclear Localization ◽  
Nuclear Import ◽  
Nuclear Localization Signal ◽  
Matrix Protein ◽  
Computer Assisted ◽  
Viral Dna ◽  
Immunodeficiency Virus ◽  
Localization Signal ◽  
Hiv 1

ABSTRACT Despite recent progress in anti-human immunodeficiency virus (HIV) therapy, drug toxicity and emergence of drug-resistant isolates during long-term treatment of HIV-infected patients necessitate the search for new targets that can be used to develop novel antiviral agents. One such target is the process of nuclear translocation of the HIV preintegration complex. Previously we described a class of arylene bis(methylketone) compounds that inhibit HIV-1 nuclear import by targeting the nuclear localization signal (NLS) in the matrix protein (MA). Here we report a different class of MA NLS-targeting compounds that was selected using computer-assisted drug design. The leading compound from this group, ITI-367, showed potent anti-HIV activity in cultures of T lymphocytes and macrophages and also inhibited HIV-1 replication in ex vivo cultured lymphoid tissue. The virus carrying inactivating mutations in MA NLS was resistant to ITI-367. Analysis by real-time PCR demonstrated that the compound specifically inhibited nuclear import of viral DNA, measured by two-long terminal repeat circle formation. Evidence of the existence of this mechanism was provided by immunofluorescent microscopy, using fluorescently labeled HIV-1, which demonstrated retention of the viral DNA in the cytoplasm of drug-treated macrophages. Compounds inhibiting HIV-1 nuclear import may be attractive candidates for further development.

scholarly journals Evolutionary Selection of the Nuclear Localization Signal in the Viral Nucleoprotein Leads to Host Adaptation of the Genus Orthobornavirus

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1291
Author(s):  
Ryo Komorizono ◽  
Yukiko Sassa ◽  
Masayuki Horie ◽  
Akiko Makino ◽  
Keizo Tomonaga
Keyword(s):  
Host Range ◽  
Nuclear Localization ◽  
Nuclear Localization Signal ◽  
Mammalian Cells ◽  
Matrix Protein ◽  
Host Adaptation ◽  
Host Cells ◽  
Viral Glycoprotein ◽  
Mammalian Cell Lines ◽  
Localization Signal

Adaptation of the viral life cycle to host cells is necessary for efficient viral infection and replication. This evolutionary process has contributed to the mechanism for determining the host range of viruses. Orthobornaviruses, members of the family Bornaviridae, are non-segmented, negative-strand RNA viruses, and several genotypes have been isolated from different vertebrate species. Previous studies revealed that some genotypes isolated from avian species can replicate in mammalian cell lines, suggesting the zoonotic potential of avian orthobornaviruses. However, the mechanism by which the host specificity of orthobornaviruses is determined has not yet been identified. In this study, we found that the infectivity of orthobornaviruses is not determined at the viral entry step, mediated by the viral glycoprotein and matrix protein. Furthermore, we demonstrated that the nuclear localization signal (NLS) sequence in the viral nucleoprotein (N) has evolved under natural selection and determines the host-specific viral polymerase activity. A chimeric mammalian orthobornavirus, which has the NLS sequence of avian orthobornavirus N, exhibited a reduced propagation efficiency in mammalian cells. Our findings indicated that nuclear transport of the viral N is a determinant of the host range of orthobornaviruses, providing insights into the evolution and host adaptation of orthobornaviruses.

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