Validation of the SCID-hu Thy/Liv mouse model with four classes of licensed antiretrovirals.
BACKGROUND
The SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals.


RESULTS
Endpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection of infected thymocytes by intracellular staining for Gag-p24. Antiviral protection from HIV-1-mediated thymocyte depletion was assessed by multicolor flow cytometric analysis of thymocyte subpopulations based on surface expression of CD3, CD4, and CD8. These mice can be productively infected with molecular clones of HIV-1 (e.g., the X4 clone NL4-3) as well as with primary R5 and R5X4 isolates. To determine whether results in this model are concordant with those found in humans, we performed direct comparisons of two drugs in the same class, each of which has known potency and dosing levels in humans. Here we show that second-generation antiretrovirals were, as expected, more potent than their first-generation predecessors: emtricitabine was more potent than lamivudine, efavirenz was more potent than nevirapine, and atazanavir was more potent than indinavir. After interspecies pharmacodynamic scaling, the dose ranges found to inhibit viral replication in the SCID-hu Thy/Liv mouse were similar to those used in humans. Moreover, HIV-1 replication in these mice was genetically stable; treatment of the mice with lamivudine did not result in the M184V substitution in reverse transcriptase, and the multidrug-resistant NY index case HIV-1 retained its drug-resistance substitutions.


CONCLUSIONS
Given the fidelity of such comparisons, we conclude that this highly reproducible mouse model is likely to predict clinical antiviral efficacy in humans.
Gladstone Institute of Virology and Immunology, University of California at San Francisco, San Francisco, California, United States of America. cheryl.stoddart@ucsf.edu
Cheryl A
CA
Stoddart
Cheryl A
CA
Bales
Jennifer C
JC
Bare
George
G
Chkhenkeli
Sofiya A
SA
Galkina
April N
AN
Kinkade
Mary E
ME
Moreno
José M
JM
Rivera
Rollie E
RE
Ronquillo
Barbara
B
Sloan
Paul L
PL
Black
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics; D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D004279:DNA, Viral / Q000235:genetics; D004195:Disease Models, Animal; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D051379:Mice; D016513:Mice, SCID / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D004279:DNA, Viral; D015395:Histocompatibility Antigens Class I; D012367:RNA, Viral