Variation of human immunodeficiency virus type-1 reverse transcriptase within the simian immunodeficiency virus genome of RT-SHIV.
RT-SHIV is a chimera of simian immunodeficiency virus (SIV) containing the reverse transcriptase (RT)-encoding region of human immunodeficiency virus type 1 (HIV-1) within the backbone of SIVmac239. It has been used in a non-human primate model for studies of non-nucleoside RT inhibitors (NNRTI) and highly active antiretroviral therapy (HAART). We and others have identified several mutations that arise in the "foreign" HIV-1 RT of RT-SHIV during in vivo replication. In this study we catalogued amino acid substitutions in the HIV-1 RT and in regions of the SIV backbone with which RT interacts that emerged 30 weeks post-infection from seven RT-SHIV-infected rhesus macaques. The virus set points varied from relatively high virus load, moderate virus load, to undetectable virus load. The G196R substitution in RT was detected from 6 of 7 animals at week 4 post-infection and remained in virus from 4 of 6 animals at week 30. Virus from four high virus load animals showed several common mutations within RT, including L74V or V75L, G196R, L214F, and K275R. The foreign RT from high virus load isolates exhibited as much variation as that of the highly variable envelope surface glycoprotein, and 10-fold higher than that of the native RT of SIVmac239. Isolates from moderate virus load animals showed much less variation in the foreign RT than the high virus load isolates. No variation was found in SIVmac239 genes known to interact with RT. Our results demonstrate substantial adaptation of the foreign HIV-1 RT in RT-SHIV-infected macaques, which most likely reflects selective pressure upon the foreign RT to attain optimal activity within the context of the chimeric RT-SHIV and the rhesus macaque host.
Center for Comparative Medicine, University of California Davis, Davis, California, United States of America.
Debra A
DA
Wadford
Center for Comparative Medicine, University of California Davis, Davis, California, United States of America.
Robert C
RC
Kauffman
Center for Comparative Medicine, University of California Davis, Davis, California, United States of America.
Jesse D
JD
Deere
Center for Comparative Medicine, University of California Davis, Davis, California, United States of America.
Scott T
ST
Aoki
Children's Center for Drug Discovery (CDD), Departments of Pediatrics and Biomedical Informatics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Richard A
RA
Stanton
Center for Comparative Medicine, University of California Davis, Davis, California, United States of America.
Joanne
J
Higgins
California National Primate Research Center, University of California Davis, Davis, California, United States of America.
Koen K A
KK
Van Rompay
Center for Comparative Medicine, University of California Davis, Davis, California, United States of America.
Andradi
A
Villalobos
Children's Center for Drug Discovery (CDD), Departments of Pediatrics and Biomedical Informatics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
James H
JH
Nettles
Emory University School of Medicine, Veterans Affairs Medical Center, Decatur, Georgia, United States of America.
Raymond F
RF
Schinazi
Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
Niels C
NC
Pedersen
Center for Comparative Medicine, University of California Davis, Davis, California, United States of America ; Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
Thomas W
TW
North
D019943:Amino Acid Substitution; D000818:Animals; D023241:Antiretroviral Therapy, Highly Active; D002478:Cells, Cultured; D005260:Female; D016679:Genome, Viral / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D017434:Protein Structure, Tertiary; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D012194:RNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors; D016097:Simian Acquired Immunodeficiency Syndrome / Q000201:enzymology / Q000235:genetics* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000201:enzymology / Q000235:genetics*; D019562:Viral Load / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000235:genetics
D012367:RNA, Viral; D011993:Recombinant Fusion Proteins; D018894:Reverse Transcriptase Inhibitors; D014764:Viral Proteins; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase