Extensive polymorphisms observed in HIV–1 clade B protease gene using high–density oligonucleotide arrays

Naturally occurring mutations in HIV–1–infected patients have important implications for therapy and the outcome of clinical studies. However, little is known about the prevalence of mutations that confer resistance to HIV–1 protease inhibitors in isolates derived from patients naive for such inhibitors. In the first clinical application of high–density oligonucleotide arraysequencing, the sequences of 167 viral isolates from 102 patients have been determined. The DNA sequence of USA HIV–1 clade B proteases was found to be extremely variable and 47.% of the 99 amino acid positions varied. This level of amino acid diversity is greater than that previously known for all worldwide HIV–1 clades combined (40%). Many of the amino acid changes that are known to contribute to drug resistance occurred as natural polymorphisms in isolates from patients who had never received protease inhibitors.

[1]  T. Miyata,et al.  Retroviral protease-like sequence in the yeast transposon Ty 1 , 1985, Nature.

[2]  Mark L. Pearson,et al.  Complete nucleotide sequence of the AIDS virus, HTLV-III , 1985, Nature.

[3]  K. Steimer,et al.  Nucleotide sequence and expression of an AIDS-associated retrovirus (ARV-2). , 1985, Science.

[4]  Gilcher Ro.  Human retroviruses and AIDS. , 1988 .

[5]  S. L. Le Grice,et al.  Active site mutagenesis of the AIDS virus protease and its alleviation by trans complementation. , 1988, The EMBO journal.

[6]  L J Davis,et al.  Active human immunodeficiency virus protease is required for viral infectivity. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[7]  B. Ho,et al.  Role of human immunodeficiency virus type 1-specific protease in core protein maturation and viral infectivity , 1989, Journal of virology.

[8]  Maria Miller,et al.  Crystal structure of a retroviral protease proves relationship to aspartic protease family , 1989, Nature.

[9]  S. P. Fodor,et al.  Light-directed, spatially addressable parallel chemical synthesis. , 1991, Science.

[10]  D. Richman,et al.  Use of self-sustained sequence replication amplification reaction to analyze and detect mutations in zidovudine-resistant human immunodeficiency virus. , 1991, The Journal of infectious diseases.

[11]  T. Kunkel,et al.  DNA polymerase fidelity and the polymerase chain reaction. , 1991, PCR methods and applications.

[12]  E. G. Shpaer,et al.  Genetic relationships determined by a DNA heteroduplex mobility assay: analysis of HIV-1 env genes. , 1993, Science.

[13]  Robert J. Lipshutz,et al.  Advanced DNA sequencing technologies , 1994 .

[14]  S. P. Fodor,et al.  Light-generated oligonucleotide arrays for rapid DNA sequence analysis. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[15]  L. Everitt,et al.  Selection of multiple human immunodeficiency virus type 1 variants that encode viral proteases with decreased sensitivity to an inhibitor of the viral protease. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[16]  D Norbeck,et al.  Characterization of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor , 1994, Journal of virology.

[17]  J. Coffin,et al.  HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy , 1995, Science.

[18]  C. Richardson,et al.  A single residue in DNA polymerases of the Escherichia coli DNA polymerase I family is critical for distinguishing between deoxy- and dideoxyribonucleotides. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[19]  J. Condra,et al.  In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors , 1995, Nature.

[20]  D. Pillay,et al.  HIV‐1 Protease inhibitors: Their development, mechanism of action and clinical potential , 1995 .

[21]  S. P. Fodor,et al.  Using oligonucleotide probe arrays to access genetic diversity. , 1995, BioTechniques.

[22]  B. Larder,et al.  Mutations in RT and Protease III -93 NOV 95 Mutations in HIV-1 Reverse Transcriptase and Protease Associated with Drug Resistance , 1996 .