Suppression of Human Immunodeficiency Virus Type 1 (HIV-1) Viremia with Reverse Transcriptase and Integrase Inhibitors, CD4+ T-Cell Recovery, and Viral Rebound upon Interruption of Therapy in a New Model for HIV Treatment in the Humanized Rag2-/-γc-/- Mouse

被引:60
作者
Choudhary, Shailesh K. [1 ]
Rezk, Naser L. [2 ]
Ince, William L. [3 ]
Cheema, Manzoor [1 ]
Zhang, Liguo [4 ]
Su, Lishan [3 ,4 ]
Swanstrom, Ronald [3 ]
Kashuba, Angela D. M. [2 ]
Margolis, David M. [1 ,4 ,5 ]
机构
[1] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA
[3] Univ N Carolina, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA
[4] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA
[5] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA
关键词
IN-VITRO; ANTIRETROVIRAL THERAPY; RHESUS MACAQUES; MICE; INFECTION; TRANSMISSION; TENOFOVIR; EMTRICITABINE; REPLICATION; RALTEGRAVIR;
D O I
10.1128/JVI.00580-09
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
A small animal model that reproduces human immunodeficiency virus type 1 (HIV-1) pathogenesis may allow modeling of new therapeutic strategies in ways not approachable in mononuclear cell culture. We find that, as in humans, combination antiretroviral therapy (ART) in humanized (hu-) Rag2(-/-)gamma(-/-)(c) mice allows suppression of viremia below the limits of detection and recovery of CD4(+) cells, while interruption of ART results in viral rebound and renewed loss of CD4(+) T cells. Failure of ART in infected mice is associated with the appearance of drug resistance mutations. The hu-Rag2(-/-)gamma(-/-)(c) mouse may therefore facilitate testing of novel approaches to HIV replication and persistence.
引用
收藏
页码:8254 / 8258
页数:5
相关论文
共 23 条
[1]   In vitro characterization of a simian immunodeficiency virus-human immunodeficiency virus (HIV) chimera expressing HIV type 1 reverse transcriptase to study antiviral resistance in pigtail macaques [J].
Ambrose, Z ;
Boltz, V ;
Palmer, S ;
Coffin, JM ;
Hughes, SH ;
KewalRamani, VN .
JOURNAL OF VIROLOGY, 2004, 78 (24) :13553-13561
[2]   Suppression of viremia and evolution of human immunodeficiency virus type 1 drug resistance in a macaque model for Antiretroviral therapy [J].
Ambrose, Zandrea ;
Palmer, Sarah ;
Boltz, Valerie F. ;
Kearney, Mary ;
Larsen, Kay ;
Polacino, Patricia ;
Flanary, Leon ;
Oswald, Kelli ;
Piatak, Michael, Jr. ;
Smedley, Jerem ;
Shao, Wei ;
Bischofberger, Norbert ;
Maldarelli, Frank ;
Kimata, Jason T. ;
Mellors, John W. ;
Hu, Shiu-Lok ;
Coffin, John M. ;
Lifson, Jeffrey D. ;
KewalRamani, Vineet N. .
JOURNAL OF VIROLOGY, 2007, 81 (22) :12145-12155
[3]   Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2-/-γc-/- mice [J].
Baenziger, Stefan ;
Tussiwand, Roxane ;
Schlaepfer, Erika ;
Mazzucchelli, Luca ;
Heikenwalder, Mathias ;
Kurrer, Michael O. ;
Behnke, Silvia ;
Frey, Joachim ;
Oxenius, Annette ;
Joller, Helen ;
Aguzzi, Adriano ;
Manz, Markus G. ;
Speck, Roberto F. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (43) :15951-15956
[4]   Mucosal transmission of R5 and X4 tropic HIV-1 via vaginal and rectal routes in humanized Rag-/- γc-/- (RAG-hu) mice [J].
Berges, Bradford K. ;
Akkina, Sarah R. ;
Folkvord, Joy M. ;
Connick, Elizabeth ;
Akkina, Ramesh .
VIROLOGY, 2008, 373 (02) :342-351
[5]   HIV-1 infection and CD4 T cell depletion in the humanized Rag2-/-γc-/- (RAG-hu) mouse model [J].
Berges, Bradford K. ;
Wheat, William H. ;
Palmer, Brent E. ;
Connick, Elizabeth ;
Akkina, Ramesh .
RETROVIROLOGY, 2006, 3 (1)
[6]   Steady-state pharmacokinetics of emtricitabine and tenofovir disoproxil fumarate administered alone and in combination in healthy volunteers [J].
Blum, M. Robert ;
Chittick, Gregory E. ;
Begley, John A. ;
Zong, Jian .
JOURNAL OF CLINICAL PHARMACOLOGY, 2007, 47 (06) :751-759
[7]   Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice [J].
Denton, Paul W. ;
Estes, Jacob D. ;
Sun, Zhifeng ;
Othieno, Florence A. ;
Wei, Bangdong L. ;
Wege, Anja K. ;
Powell, Daniel A. ;
Payne, Deborah ;
Haase, Ashley T. ;
Garcia, J. Victor .
PLOS MEDICINE, 2008, 5 (01) :79-89
[8]   IDENTIFICATION OF CONSERVED AMINO-ACID-RESIDUES CRITICAL FOR HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INTEGRASE FUNCTION-INVITRO [J].
ENGELMAN, A ;
CRAIGIE, R .
JOURNAL OF VIROLOGY, 1992, 66 (11) :6361-6369
[9]   Effects of mutations in residues near the active site of human immunodeficiency virus type 1 integrase on specific enzyme-substrate interactions [J].
Gerton, JL ;
Ohgi, S ;
Olsen, M ;
Derisi, J ;
Brown, PO .
JOURNAL OF VIROLOGY, 1998, 72 (06) :5046-5055
[10]   Antiretroviral treatment of adult HIV infection - 2008 recommendations of the International AIDS Society USA panel [J].
Hammer, Scott M. ;
Eron, Joseph J., Jr. ;
Reiss, Peter ;
Schooley, Robert T. ;
Thompson, Melanie A. ;
Walmsley, Sharon ;
Cahn, Pedro ;
Fischl, Margaret A. ;
Gatell, Jose M. ;
Hirsch, Martin S. ;
Jacobsen, Donna M. ;
Montaner, Julio S. G. ;
Richman, Douglas D. ;
Yeni, Patrick G. ;
Volberding, Paul A. .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2008, 300 (05) :555-570