Compatibility of Tat and Rev transactivators in the primate lentiviruses

Sakai, Hiroyuki; Sakuragi, Jun-ichi; Sakuragi, Sayuri; Kawamura, Minoru; Adachi, Akio

doi:10.1007/bf01316880

Cited by 15 publications

(14 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Replication in "non-permissive" cells, such as primary T lymphocytes, macrophages, and certain T cell lines, is strictly dependent on Vif, whereas Vif is dispensable for replication in "permissive" cell lines, such as 293T cells (13,14). APOBEC3G expression is restricted to non-permissive cells (3), whereas its expression in permissive cells confers a non-permissive phenotype (3, 6 -9).…”

mentioning

confidence: 99%

Vif Overcomes the Innate Antiviral Activity of APOBEC3G by Promoting Its Degradation in the Ubiquitin-Proteasome Pathway

Mehle

Strack

Ancuța

et al. 2004

Journal of Biological Chemistry

432

380

View full text Add to dashboard Cite

Viruses must overcome diverse intracellular defense mechanisms to establish infection. The Vif (virion infectivity factor) protein of human immunodeficiency virus 1 (HIV-1) acts by overcoming the antiviral activity of APOBEC3G (CEM15), a cytidine deaminase that induces G to A hypermutation in newly synthesized viral DNA. In the absence of Vif, APOBEC3G incorporation into virions renders HIV-1 non-infectious. We report here that Vif counteracts the antiviral activity of APOBEC3G by targeting it for destruction by the ubiquitin-proteasome pathway. Vif forms a complex with APOBEC3G and enhances APOBEC3G ubiquitination, resulting in reduced steady-state APOBEC3G levels and a decrease in protein half-life. Furthermore, Vif-dependent degradation of APOBEC3G is blocked by proteasome inhibitors or ubiquitin mutant K48R. A mutation of highly conserved cysteines or the deletion of a conserved SLQ(Y/F)LA motif in Vif results in mutants that fail to induce APOBEC3G degradation and produce non-infectious HIV-1; however, mutations of conserved phosphorylation sites in Vif that impair viral replication do not affect APOBEC3G degradation, suggesting that Vif is important for other functions in addition to inducing proteasomal degradation of APOBEC3G. Vif is monoubiquitinated in the absence of APOBEC3G but is polyubiquitinated and rapidly degraded when APOBEC3G is coexpressed, suggesting that coexpression accelerates the degradation of both proteins. These results suggest that Vif functions by targeting APOBEC3G for degradation via the ubiquitin-proteasome pathway and implicate the proteasome as a site of dynamic interplay between microbial and cellular defenses.

show abstract

mentioning

confidence: 99%

Vif Overcomes the Innate Antiviral Activity of APOBEC3G by Promoting Its Degradation in the Ubiquitin-Proteasome Pathway

Mehle

Strack

Ancuța

et al. 2004

Journal of Biological Chemistry

432

380

View full text Add to dashboard Cite

show abstract

“…HIV-1 genomes that do not express Vif (⌬Vif) fail to replicate in primary T cells, macrophages, and some ''nonpermissive'' T cell lines (12,13). Other ''permissive'' T cell lines, such as 293T cells, can support the replication of ⌬Vif HIV-1 genomes (14).…”

mentioning

confidence: 99%

A single amino acid substitution in human APOBEC3G antiretroviral enzyme confers resistance to HIV-1 virion infectivity factor-induced depletion

Svarovskaia

Barr

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

224

242

View full text Add to dashboard Cite

HIV-1 and other retroviruses occasionally undergo hypermutation, characterized by a high rate of G-to-A substitution. Recently, the human apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G (APOBEC3G), first identified as CEM15, was shown to be packaged into retroviral virions and to deaminate deoxycytidine to deoxyuridine in newly synthesized viral minusstrand DNA, thereby inducing G-to-A hypermutation. This innate mechanism of resistance to retroviral infection is counteracted by the HIV-1 viral infectivity factor (Vif), which protects the virus by preventing the incorporation of APOBEC3G into virions by rapidly inducing its ubiquitination and proteasomal degradation. To gain insights into the mechanism by which Vif protects HIV-1 from APOBEC3G, we substituted several amino acids in human APOBEC3G with equivalent residues in simian APOBEC3Gs that are resistant to HIV-1 Vif and determined the effects of the mutations on HIV-1 replication in the presence and absence of Vif. We found that a single amino acid substitution mutant of human APOBEC3G (D128K) can interact with HIV-1 Vif but is not depleted from cells; thus, it inhibits HIV-1 replication in an HIV-1 Vif-resistant manner. Interestingly, rhesus macaque simian immunodeficiency virus 239 or HIV-2 Vif coexpression depleted the intracellular steady state levels of the D128K mutant and abrogated its antiviral activity, indicating that it can be a substrate for the proteasomal pathway. The HIV-1 Vif-resistant mutant APOBEC3G could provide a gene therapy approach to combat HIV-1 infection.

show abstract

“…The requirement for Vif differs among cell lines (2,4,6,8,9). Recent studies suggest that Vif enhances infectivity by overcoming an inhibitory factor present in nonpermissive cells (53,54).…”

Section: Discussionmentioning

confidence: 99%

“…Vif (virion infectivity factor) is essential for the establishment of productive infection of HIV-1 in peripheral blood lymphocytes and macrophages in vitro and for pathogenesis in animal models of AIDS (1)(2)(3)(4)(5)(6)(7). In cell culture, vif-defective HIV-1 is able to replicate in some T-lymphoblastoid cell lines termed permissive (CEM-SS, SupT1, C8166, and Jurkat), whereas Vif is required in other cell lines, such as H9, U38, or MT-2, termed nonpermissive (2,4,6,8,9). Vif acts during late steps of the viral life cycle to increase the infectivity of HIV-1 virus particles as much as 100 -1000-fold.…”

Section: Human Immunodeficiency Virus Type 1 (Hiv-1)mentioning

confidence: 99%

“…Inhibition of HIV-1 Viral Infectivity by Anti-Vif I4BL Is Specific for Nonpermissive Cells-Vif modulates HIV-1 infection in cultured T-cell lines in a cell-dependent manner (2,4,6,8,9). To evaluate the specificity of viral inhibition in different cell lines, a recombinant HIV-1 expressing I4BL or anti-thyroglobulin scFv in cis was generated.…”

Section: H9 Cells Expressing Vif-specific Intrabody I4bl Are Protectementioning

confidence: 99%

See 1 more Smart Citation

Functional Neutralization of HIV-1 Vif Protein by Intracellular Immunization Inhibits Reverse Transcription and Viral Replication

Gonçalves¹,

Silva²,

Freitas-Vieira³

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Compatibility of Tat and Rev transactivators in the primate lentiviruses

Cited by 15 publications

References 38 publications

Vif Overcomes the Innate Antiviral Activity of APOBEC3G by Promoting Its Degradation in the Ubiquitin-Proteasome Pathway

Vif Overcomes the Innate Antiviral Activity of APOBEC3G by Promoting Its Degradation in the Ubiquitin-Proteasome Pathway

A single amino acid substitution in human APOBEC3G antiretroviral enzyme confers resistance to HIV-1 virion infectivity factor-induced depletion

Functional Neutralization of HIV-1 Vif Protein by Intracellular Immunization Inhibits Reverse Transcription and Viral Replication

Contact Info

Product

Resources

About