Dynamics of HIV-1 recombination in its natural target cells

被引:344
作者
Levy, DN
Aldrovandi, GM
Kutsch, O
Shaw, GM
机构
[1] Univ Alabama, Dept Med, Birmingham, AL 35294 USA
[2] Univ Alabama, Dept Pediat Infect Dis, Birmingham, AL 35294 USA
[3] Univ Alabama, Howard Hughes Med Inst, Birmingham, AL 35294 USA
关键词
D O I
10.1073/pnas.0306764101
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Genetic recombination is believed to assist HIV-1 diversification and escape from host immunity and antiviral therapies, yet this process remains largely unexamined within the natural target-cell populations. We developed a method for measuring HIV-1 recombination directly that employs reporter viruses bearing functional enhanced yellow fluorescent protein (YFP) and enhanced cyan fluorescent protein (CFP) genes in which recombination produces a modified GFP gene and GFP fluorescence in the infected cells. These reporter viruses allow simultaneous quantification of the dynamics of HIV-1 infection, coinfection, and recombination in cell culture and in animal models by flow-cytometric analysis. Multi-round infection assays revealed that productive cellular coinfection was subject to little functional inhibition. As a result, generation of recombinants proceeded according to the square of the infection rate during HIV-1 replication in T lymphocytes and within human thymic grafts in severe combined immunodeficient (SCID)-hu (Thy/Liv) mice. These results suggest that increases in viral load may confer a compounding risk of virus escape by means of recombinational diversification. A single round of replication in T lymphocytes in culture generated an average of nine recombination events per virus, and infection of macrophages led to approximate to30 crossover events, making HIV-1 up to an order of magnitude more recombinogenic than recognized previously and demonstrating that the infected cell exerts a profound influence on the frequency of recombination.
引用
收藏
页码:4204 / 4209
页数:6
相关论文
共 43 条
[1]   PRODUCTION OF ACQUIRED IMMUNODEFICIENCY SYNDROME-ASSOCIATED RETROVIRUS IN HUMAN AND NONHUMAN CELLS TRANSFECTED WITH AN INFECTIOUS MOLECULAR CLONE [J].
ADACHI, A ;
GENDELMAN, HE ;
KOENIG, S ;
FOLKS, T ;
WILLEY, R ;
RABSON, A ;
MARTIN, MA .
JOURNAL OF VIROLOGY, 1986, 59 (02) :284-291
[2]   THE SCID-HU MOUSE AS A MODEL FOR HIV-1 INFECTION [J].
ALDROVANDI, GM ;
FEUER, G ;
GAO, LY ;
JAMIESON, B ;
KRISTEVA, M ;
CHEN, ISY ;
ZACK, JA .
NATURE, 1993, 363 (6431) :732-736
[3]   Virus evolution - The importance of being erroneous [J].
Bonhoeffer, S ;
Sniegowski, P .
NATURE, 2002, 420 (6914) :367-+
[4]   Recombination in HIV and the evolution of drug resistance:: for better or for worse? [J].
Bretscher, MT ;
Althaus, CL ;
Müller, V ;
Bonhoeffer, S .
BIOESSAYS, 2004, 26 (02) :180-188
[5]   STRUCTURE, REPLICATION, AND RECOMBINATION OF RETROVIRUS GENOMES - SOME UNIFYING HYPOTHESES [J].
COFFIN, JM .
JOURNAL OF GENERAL VIROLOGY, 1979, 42 (JAN) :1-26
[6]   HIV POPULATION-DYNAMICS IN-VIVO - IMPLICATIONS FOR GENETIC-VARIATION, PATHOGENESIS, AND THERAPY [J].
COFFIN, JM .
SCIENCE, 1995, 267 (5197) :483-489
[7]   A combinatorial ledge: reverse transcriptase fidelity, total body viral burden, and the implications of multiple-drug HIV therapy for the evolution of antiviral resistance [J].
Colgrove, R ;
Japour, A .
ANTIVIRAL RESEARCH, 1999, 41 (01) :45-56
[8]   REQUIREMENTS FOR STRAND TRANSFER BETWEEN INTERNAL REGIONS OF HETEROPOLYMER TEMPLATES BY HUMAN-IMMUNODEFICIENCY-VIRUS REVERSE-TRANSCRIPTASE [J].
DESTEFANO, JJ ;
MALLABER, LM ;
RODRIGUEZRODRIGUEZ, L ;
FAY, PJ ;
BAMBARA, RA .
JOURNAL OF VIROLOGY, 1992, 66 (11) :6370-6378
[9]   Viruses at the edge of adaptation [J].
Domingo, E .
VIROLOGY, 2000, 270 (02) :251-253
[10]   Error catastrophe and antiviral strategy [J].
Eigen, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (21) :13374-13376