scholarly journals Antiretroviral Activity of Ancestral TRIM5α

2007 ◽  
Vol 82 (5) ◽  
pp. 2089-2096 ◽  
Author(s):  
Valérie Goldschmidt ◽  
Angela Ciuffi ◽  
Millan Ortiz ◽  
David Brawand ◽  
Miguel Muñoz ◽  
...  
Keyword(s):  
Leukemia Virus ◽  
Restriction Pattern ◽  
Bayesian Approaches ◽  
Old World ◽  
Ancestral Sequences ◽  
Immunodeficiency Virus ◽  
The Common ◽  
Hiv 1 ◽  
Antiretroviral Activity

ABSTRACT The antiretroviral protein TRIM5α is known to have evolved different restriction capacities against various retroviruses, driven by positive Darwinian selection. However, how these different specificities have evolved in the primate lineages is not fully understood. Here we used ancestral protein resurrection to estimate the evolution of antiviral restriction specificities of TRIM5α on the primate lineage leading to humans. We used TRIM5α coding sequences from 24 primates for the reconstruction of ancestral TRIM5α sequences using maximum-likelihood and Bayesian approaches. Ancestral sequences were transduced into HeLa and CRFK cells. Stable cell lines were generated and used to test restriction of a panel of extant retroviruses (human immunodeficiency virus type 1 [HIV-1] and HIV-2, simian immunodeficiency virus [SIV] variants SIVmac and SIVagm, and murine leukemia virus [MLV] variants N-MLV and B-MLV). The resurrected TRIM5α variant from the common ancestor of Old World primates (Old World monkeys and apes, ∼25 million years before present) was effective against present day HIV-1. In contrast to the HIV-1 restriction pattern, we show that the restriction efficacy against other retroviruses, such as a murine oncoretrovirus (N-MLV), is higher for more recent resurrected hominoid variants. Ancestral TRIM5α variants have generally limited efficacy against HIV-2, SIVagm, and SIVmac. Our study sheds new light on the evolution of the intrinsic antiviral defense machinery and illustrates the utility of functional evolutionary reconstruction for characterizing recently emerged protein differences.

scholarly journals Identification of APOBEC3DE as Another Antiretroviral Factor from the Human APOBEC Family

2006 ◽  
Vol 80 (21) ◽  
pp. 10522-10533 ◽  
Author(s):  
Ying Dang ◽  
Xiaojun Wang ◽  
Walter J. Esselman ◽  
Yong-Hui Zheng
Keyword(s):  
Cytidine Deaminase ◽  
Chromosome 22 ◽  
Site Specificity ◽  
Virion Infectivity Factor ◽  
Immunodeficiency Virus ◽  
Novel Target ◽  
Apobec Family ◽  
Hiv 1 ◽  
Antiretroviral Activity

ABSTRACT A tandem arrayed gene cluster encoding seven cytidine deaminase genes is present on human chromosome 22. These are APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3DE, APOBEC3F, APOBEC3G, and APOBEC3H. Three of them, APOBEC3G, APOBEC3F, and APOBEC3B, block replication of human immunodeficiency virus type 1 (HIV-1) and many other retroviruses. In addition, APOBEC3A and APOBEC3C block intracellular retrotransposons and simian immunodeficiency virus (SIV), respectively. In opposition to APOBEC genes, HIV-1 and SIV contain a virion infectivity factor (Vif) that targets APOBEC3F and APOBEC3G for polyubiquitylation and proteasomal degradation. Herein, we studied the antiretroviral activities of the human APOBEC3DE and APOBEC3H. We found that only APOBEC3DE had antiretroviral activity for HIV-1 or SIV and that Vif suppressed this antiviral activity. APOBEC3DE was encapsidated and capable of deaminating cytosines to uracils on viral minus-strand DNA, resulting in disruption of the viral life cycle. Other than GG-to-AG and AG-to-AA mutations, it had a novel target site specificity, resulting in introduction of GC-to-AC mutations on viral plus-strand DNA. Such mutations have been detected previously in HIV-1 clinical isolates. In addition, APOBEC3DE was expressed much more extensively than APOBEC3F in various human tissues and it formed heteromultimers with APOBEC3F or APOBEC3G in the cell. From these studies, we concluded that APOBEC3DE is a new contributor to the intracellular defense network, resulting in suppression of retroviral invasion.

scholarly journals Evidence that Ecotropic Murine Leukemia Virus Contamination in TZM-bl Cells Does Not Affect the Outcome of Neutralizing Antibody Assays with Human Immunodeficiency Virus Type 1

2009 ◽  
Vol 83 (16) ◽  
pp. 8289-8292 ◽  
Author(s):  
Emily J. Platt ◽  
Miroslawa Bilska ◽  
Susan L. Kozak ◽  
David Kabat ◽  
David C. Montefiori
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cell Line ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Murine Leukemia

ABSTRACT The TZM-bl cell line that is commonly used to assess neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) was recently reported to be contaminated with an ecotropic murine leukemia virus (MLV) (Y. Takeuchi, M. O. McClure, and M. Pizzato, J. Virol. 82:12585-12588, 2008), raising questions about the validity of results obtained with this cell line. Here we confirm this observation and show that HIV-1 neutralization assays performed with a variety of serologic reagents in a similar cell line that does not harbor MLV yield results that are equivalent to those obtained in TZM-bl cells. We conclude that MLV contamination has no measurable effect on HIV-1 neutralization when TZM-bl cells are used as targets for infection.

scholarly journals Coding Sequences Upstream of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Domain in Gag-Pol Are Not Essential for Incorporation of the Pr160gag-pol into Virus Particles

2002 ◽  
Vol 76 (7) ◽  
pp. 3221-3231 ◽  
Author(s):  
Hsu-Chen Chiu ◽  
Szu-Yung Yao ◽  
Chin-Tien Wang
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Leukemia Virus ◽  
Deletion Mutants ◽  
Coding Region ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Incorporation of the human immunodeficiency virus type 1 (HIV-1) Gag-Pol into virions is thought to be mediated by the N-terminal Gag domain via interaction with the Gag precursor. However, one recent study has demonstrated that the murine leukemia virus Pol can be incorporated into virions independently of Gag-Pol expression, implying a possible interaction between the Pol and Gag precursor. To test whether the HIV-1 Pol can be incorporated into virions on removal of the N-terminal Gag domain and to define sequences required for the incorporation of Gag-Pol into virions in more detail, a series of HIV Gag-Pol expression plasmids with various extensive deletions in the region upstream of the reverse transcriptase (RT) domain was constructed, and viral incorporation of the Gag-Pol deletion mutants was examined by cotransfecting 293T cells with a plasmid expressing Pr55 gag . Analysis indicated that deletion of the N-terminal two-thirds of the gag coding region did not significantly affect the incorporation of Gag-Pol into virions. In contrast, Gag-Pol proteins with deletions covering the capsid (CA) major homology regions and the adjacent C-terminal CA regions were impaired with respect to assembly into virions. However, Gag-Pol with sequences deleted upstream of the protease, or of the RT domain but retaining 15 N-terminal gag codons, could still be rescued into virions at a level about 20% of the wild-type level. When assayed in a nonmyristylated Gag-Pol context, all of the Gag-Pol deletion mutants were incorporated into virions at a level comparable to their myristylated counterparts, suggesting that the incorporation of the Gag-Pol deletion mutants into virions is independent of the N-terminal myristylation signal.

scholarly journals Antiretroviral Activity and Vif Sensitivity of Rhesus Macaque APOBEC3 Proteins

2007 ◽  
Vol 81 (24) ◽  
pp. 13932-13937 ◽  
Author(s):  
Cesar A. Virgen ◽  
Theodora Hatziioannou
Keyword(s):  
Human Immunodeficiency Virus ◽  
Rhesus Macaque ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Restriction Factor ◽  
Immunodeficiency Virus ◽  
Apobec3 Proteins ◽  
Hiv 1 ◽  
Antiretroviral Activity

ABSTRACT The inability of human immunodeficiency virus type 1(HIV-1) to replicate in rhesus macaque cells is in part due to the failure of HIV-1 Vif to counteract the restriction factor APOBEC3G. However, in this study we demonstrate that several rhesus macaque APOBEC3 (rhAPOBEC3) proteins are capable of inhibiting HIV-1 infectivity. There was considerable variation in the ability of a panel of Vif proteins to induce degradation of rhAPOBEC3 proteins, and mutations within HIV-1 Vif that render it capable of degrading rhAPOBEC3G did not confer activity against other antiviral rhAPOBEC3 proteins. These findings suggest that multiple APOBEC3 proteins can contribute to primate lentivirus species tropism.

scholarly journals The Eukaryotic Translation Initiation Factor 4GI Is Cleaved by Different Retroviral Proteases

2003 ◽  
Vol 77 (23) ◽  
pp. 12392-12400 ◽  
Author(s):  
Enrique Álvarez ◽  
Luis Menéndez-Arias ◽  
Luis Carrasco
Keyword(s):  
Protein Synthesis ◽  
Virus Type ◽  
Leukemia Virus ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Intact Cells ◽  
Immunodeficiency Virus ◽  
Retroviral Proteases ◽  
Hiv 1

ABSTRACT The initiation factor eIF4G plays a central role in the regulation of translation. In picornaviruses, as well as in human immunodeficiency virus type 1 (HIV-1), cleavage of eIF4G by the viral protease leads to inhibition of protein synthesis directed by capped cellular mRNAs. In the present work, cleavage of both eIF4GI and eIF4GII has been analyzed by employing the proteases encoded within the genomes of several members of the family Retroviridae, e.g., Moloney murine leukemia virus (MoMLV), mouse mammary tumor virus, human T-cell leukemia virus type 1, HIV-2, and simian immunodeficiency virus. All of the retroviral proteases examined were able to cleave the initiation factor eIF4GI both in intact cells and in cell-free systems, albeit with different efficiencies. The eIF4GI hydrolysis patterns obtained with HIV-1 and HIV-2 proteases were very similar to each other but rather different from those obtained with MoMLV protease. Both eIF4GI and eIF4GII were cleaved very efficiently by the MoMLV protease. However, eIF4GII was a poor substrate for HIV proteases. Proteolytic cleavage of eIF4G led to a profound inhibition of cap-dependent translation, while protein synthesis driven by mRNAs containing internal ribosome entry site elements remained unaffected or was even stimulated in transfected cells.

scholarly journals Disruption of Human TRIM5α Antiviral Activity by Nonhuman Primate Orthologues

2005 ◽  
Vol 79 (12) ◽  
pp. 7883-7888 ◽  
Author(s):  
Lionel Berthoux ◽  
Sarah Sebastian ◽  
David M. Sayah ◽  
Jeremy Luban
Keyword(s):  
Leukemia Virus ◽  
Coiled Coil ◽  
Cyclophilin A ◽  
Susceptibility To Infection ◽  
Coiled Coil Domain ◽  
Immunodeficiency Virus ◽  
Species Specific ◽  
Hiv 1 ◽  
Modest Effect

ABSTRACT TRIM5 is a determinant of species-specific differences in susceptibility to infection by retroviruses bearing particular capsids. Human immunodeficiency virus type 1 (HIV-1) infection is blocked by the alpha isoform of macaque TRIM5 (TRIM5αrh) or by the product of the owl monkey TRIM5-cyclophilin A gene fusion (TRIMCyp). Human TRIM5α potently restricts specific strains of murine leukemia virus (N-MLV) but has only a modest effect on HIV-1. The amino termini of TRIM5 orthologues are highly conserved and possess a coiled-coil domain that promotes homomultimerization. Here we show that heterologous expression of TRIM5αrh or TRIMCyp in human cells interferes with the anti-N-MLV activity of endogenous human TRIM5α (TRIM5αhu). Deletion of the cyclophilin domain from TRIMCyp has no effect on heteromultimerization or colocalization with TRIM5αhu but prevents interference with anti-N-MLV activity. These data demonstrate that TRIM5 orthologues form heteromultimers and indicate that C-terminal extensions alter virus recognition by multimers of these proteins.

scholarly journals Cleavage of the Murine Leukemia Virus Transmembrane Env Protein by Human Immunodeficiency Virus Type 1 Protease: Transdominant Inhibition by Matrix Mutations

1998 ◽  
Vol 72 (12) ◽  
pp. 9621-9627 ◽  
Author(s):  
Rosemary E. Kiernan ◽  
Eric O. Freed
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Env Protein ◽  
Hiv 1 ◽  
Murine Leukemia

ABSTRACT We have identified mutations in the human immunodeficiency virus type 1 (HIV-1) matrix protein (MA) which block infectivity of virions pseudotyped with murine leukemia virus (MuLV) envelope (Env) glycoproteins without affecting infectivity conferred by HIV-1 Env or vesicular stomatitis virus G glycoproteins. This inhibition is very potent and displays a strong transdominant effect; infectivity is reduced more than 100-fold when wild-type and mutant molecular clones are cotransfected at a 1:1 ratio. This phenomenon is observed with both ecotropic and amphotropic MuLV Env. The MA mutations do not affect the incorporation of MuLV Env into virions. We demonstrate that in HIV-1 virions pseudotyped with MuLV Env, the HIV-1 protease (PR) efficiently catalyzes the cleavage of the p15(E) transmembrane (TM) protein to p12(E). Immunoprecipitation analysis of pseudotyped virions reveals that the mutant MA blocks this HIV-1 PR-mediated cleavage of MuLV TM. Furthermore, the transdominant inhibition exerted by the mutant MA on wild-type infectivity correlates with the relative level of p15(E) cleavage. Consistent with the hypothesis that abrogation of infectivity imposed by the mutant MA is due to inhibition of p15(E) cleavage, mutant virions are significantly more infectious when pseudotyped with a truncated p12(E) form of MuLV Env. These results indicate that HIV-1 Gag sequences can influence the viral PR-mediated processing of the MuLV TM Env protein p15(E). These findings have implications for the development of HIV-1-based retroviral vectors pseudotyped with MuLV Env, since p15(E) cleavage is essential for activating membrane fusion and virus infectivity.

Human T-Cell Lymphotropic Virus-Type I

1990 ◽  
Vol 11 (6) ◽  
pp. 314-318 ◽  
Author(s):  
Julie Larkin ◽  
John T. Sinnott ◽  
Joshua Weiss ◽  
Douglas A. Holt
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Leukemia Virus ◽  
Type I ◽  
Adult T Cell Leukemia ◽  
Visna Virus ◽  
Human T Cell ◽  
Immunodeficiency Virus ◽  
Hiv 1

Human T-cell lymphotropic virus type-1 (HTLV-I) is a recently recognized retrovirus identified as the cause of adult T-cell leukemia-lymphoma (ATLL) and HTLV-I-associated myelopathy (TSPI HAM). HTLV-I, a member of theRetroviridaefamily of viruses, was first described in 1980 after the isolation of the virus from a patient with a T-cell lymphoma. These pathogenic retroviruses are typically divided into theOncovirinaeandLentivirinae. The oncovirus group, including HTLV-I, HTLV-II and bovine leukemia virus (BLV), is generally associated with tumors. The lentiviruses are associated with immune deficiency and/or neurologic disease, and include agents such as the visna virus of sheep and the human immunodeficiency virus type-1 and -2 HIV-1 and HIV-2).

scholarly journals Inability of Human Immunodeficiency Virus Type 1 Produced in Murine Cells To Selectively Incorporate Primer \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{tRNA}_{3}^{\mathrm{Lys}}\) \end{document}

2008 ◽  
Vol 82 (24) ◽  
pp. 12049-12059 ◽  
Author(s):  
Min Wei ◽  
Yiliang Yang ◽  
Meijuan Niu ◽  
Laurie Desfosse ◽  
Robert Kennedy ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Reverse Transcription ◽  
Leukemia Virus ◽  
Trna Synthetase ◽  
Primer Binding Site ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Attempts to use the mouse as a model system for studying AIDS are stymied by the multiple blocks to human immunodeficiency virus type 1 (HIV-1) replication that exist in mouse cells at the levels of viral entry, transcription, and Gag assembly and processing. In this report, we describe an additional block in the selective packaging of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(tRNA_{3}^{Lys}\) \end{document} into HIV-1 produced in murine cells. HIV-1 and murine leukemia virus (MuLV) use \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(tRNA_{3}^{Lys}\) \end{document} and tRNAPro, respectively, as primers for reverse transcription. Selective packaging of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(tRNA_{3}^{Lys}\) \end{document} into HIV-1 produced in human cells is much stronger than that for tRNAPro incorporation into MuLV produced in murine cells, and different packaging mechanisms are used. Thus, both lysyl-tRNA synthetase and GagPol are required for \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(tRNA_{3}^{Lys}\) \end{document} packaging into HIV-1, but neither prolyl-tRNA synthetase nor GagPol is required for tRNAPro packaging into MuLV. In this report, we show that when HIV-1 is produced in murine cells, the virus switches from an HIV-1-like incorporation of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(tRNA_{3}^{Lys}\) \end{document} to an MuLV-like packaging of tRNAPro. The primer binding site in viral RNA remains complementary to \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(tRNA_{3}^{Lys}\) \end{document} , resulting in a significant decrease in reverse transcription and infectivity. Reduction in \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(tRNA_{3}^{Lys}\) \end{document} incorporation occurs even though both murine lysyl-tRNA synthetase and HIV-1 GagPol are packaged into the HIV-1 produced in murine cells. Nevertheless, the murine cell is able to support the select incorporation of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(tRNA_{3}^{Lys}\) \end{document} into another retrovirus that uses \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(tRNA_{3}^{Lys}\) \end{document} as a primer, the mouse mammary tumor virus.

scholarly journals Analysis of the Contribution of Reverse Transcriptase and Integrase Proteins to Retroviral RNA Dimer Conformation

2005 ◽  
Vol 79 (10) ◽  
pp. 6338-6348 ◽  
Author(s):  
Penelope Buxton ◽  
Gilda Tachedjian ◽  
Johnson Mak
Keyword(s):  
Reverse Transcriptase ◽  
Leukemia Virus ◽  
Proteolytic Processing ◽  
Moloney Murine Leukemia Virus ◽  
Stable Conformation ◽  
Rna Dimerization ◽  
Immunodeficiency Virus ◽  
Rna Dimer ◽  
Hiv 1

ABSTRACT All retroviruses contain two copies of genomic RNA that are linked noncovalently. The dimeric RNA of human immunodeficiency virus type 1 (HIV-1) undergoes rearrangement during virion maturation, whereby the dimeric RNA genome assumes a more stable conformation. Previously, we have shown that the packaging of the HIV-1 polymerase (Pol) proteins reverse transcriptase (RT) and integrase (IN) is essential for the generation of the mature RNA dimer conformation. Analysis of HIV-1 mutants that are defective in processing of Pol showed that these mutant virions contained altered dimeric RNA conformation, indicating that the mature RNA dimer conformation in HIV-1 requires the correct proteolytic processing of Pol. The HIV-1 Pol proteins are multimeric in their mature enzymatically active forms; RT forms a heterodimer, and IN appears to form a homotetramer. Using RT and IN multimerization defective mutants, we have found that dimeric RNA from these mutant virions has the same stability and conformation as wild-type RNA dimers, showing that the mature enzymatically active RT and IN proteins are dispensable for the generation of mature RNA dimer conformation. This also indicated that formation of the mature RNA dimer structure occurs prior to RT or IN maturation. We have also investigated the requirement of Pol for RNA dimerization in both Mason-Pfizer monkey virus (M-PMV) and Moloney murine leukemia virus (MoMuLV) and found that in contrast to HIV-1, Pol is dispensable for RNA dimer maturation in M-PMV and MoMuLV, demonstrating that the requirement of Pol in retroviral RNA dimer maturation is not conserved among all retroviruses.

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