Reconstitution of an infectious human endogenous retrovirus

被引:228
作者
Lee, Young Nam
Bieniasz, Paul D.
机构
[1] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA
[2] Rockefeller Univ, Lab Retrovirol, New York, NY 10021 USA
关键词
D O I
10.1371/journal.ppat.0030010
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The human genome represents a fossil record of ancient retroviruses that once replicated in the ancestors of contemporary humans. Indeed, approximately 8% of human DNA is composed of sequences that are recognizably retroviral. Despite occasional reports associating human endogenous retrovirus (HERV) expression with human disease, almost all HERV genomes contain obviously inactivating mutations, and none are thought to be capable of replication. Nonetheless, one family of HERVs, namely HERV-K(HML-2), may have replicated in human ancestors less than 1 million years ago. By deriving a consensus sequence, we reconstructed a proviral clone (HERV-K-CON) that likely resembles the progenitor of HERV-K(HML-2) variants that entered the human genome within the last few million years. We show that HERV-K-CON Gag and protease proteins mediate efficient assembly and processing into retrovirus-like particles. Moreover, reporter genes inserted into the HERV-K-CON genome and packaged into HERV-K particles are capable of infectious transfer and stable integration in a manner that requires reverse transcription. Additionally, we show that HERV-K-CON Env is capable of pseudotyping HIV-1 particles and mediating entry into human and nonhuman cell lines. Furthermore, we show that HERV-K-CON is resistant to inhibition by the human retrovirus restriction factors tripartite motif 5 alpha and apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) 3G but is inhibited by APOBEC 3F. Overall, the resurrection of this extinct infectious agent in a functional form from molecular fossils should enable studies of the molecular virology and pathogenic potential of this ancient human retrovirus.
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页码:119 / 130
页数:12
相关论文
共 56 条
[1]   Retroelements and the human genome: New perspectives on an old relation [J].
Bannert, N ;
Kurth, R .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 :14572-14579
[2]   Many human endogenous retrovirus K (HERV-K) proviruses are unique to humans [J].
Barbulescu, M ;
Turner, G ;
Seaman, MI ;
Deinard, AS ;
Kidd, KK ;
Lenz, J .
CURRENT BIOLOGY, 1999, 9 (16) :861-868
[3]   High copy number in human endogenous retrovirus families is associated with copying mechanisms in addition to reinfection [J].
Belshaw, R ;
Katzourakis, A ;
Paces, J ;
Burt, A ;
Tristem, M .
MOLECULAR BIOLOGY AND EVOLUTION, 2005, 22 (04) :814-817
[4]   Genomewide screening reveals high levels of insertional polymorphism in the human endogenous retrovirus family HERV-K(HML2): Implications for present-day activity [J].
Belshaw, R ;
Dawson, ALA ;
Woolven-Allen, J ;
Redding, J ;
Burt, A ;
Tristem, M .
JOURNAL OF VIROLOGY, 2005, 79 (19) :12507-12514
[5]   Long-term reinfection of the human genome by endogenous retroviruses [J].
Belshaw, R ;
Pereira, V ;
Katzourakis, A ;
Talbot, G ;
Paces, J ;
Burt, A ;
Tristem, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (14) :4894-4899
[6]   Identification of an active reverse transcriptase enzyme encoded by a human endogenous HERV-K retrovirus [J].
Berkhout, B ;
Jebbink, M ;
Zsíros, J .
JOURNAL OF VIROLOGY, 1999, 73 (03) :2365-2375
[7]   Phenotypic heterogeneity of human endogenous retrovirus particles produced by teratocarcinoma cell lines [J].
Bieda, K ;
Hoffmann, A ;
Boller, K .
JOURNAL OF GENERAL VIROLOGY, 2001, 82 :591-596
[8]   Intrinsic immunity: a front-line defense against viral attack [J].
Bieniasz, PD .
NATURE IMMUNOLOGY, 2004, 5 (11) :1109-1115
[9]   APOBEC-mediated editing of viral RNA [J].
Bishop, KN ;
Holmes, RK ;
Sheehy, AM ;
Malim, MH .
SCIENCE, 2004, 305 (5684) :645-645
[10]   Cytidine deamination of retroviral DNA by diverse APOBEC proteins [J].
Bishop, KN ;
Holmes, RK ;
Sheehy, AM ;
Davidson, NO ;
Cho, SJ ;
Malim, MH .
CURRENT BIOLOGY, 2004, 14 (15) :1392-1396