An advanced BLT-humanized mouse model for extended HIV-1 cure studies

Kerry J. Lavender; Craig Pace; Kathrin Sutter; Ronald J. Messer; Dakota L. Pouncey; Nathan W. Cummins; Sekar Natesampillai; Jim Zheng; Joshua Goldsmith; Marek Widera; Erik S. Van Dis; Katie Phillips; Brent Race; Ulf Dittmer; George Kukolj; Kim J. Hasenkrug

doi:10.1097/QAD.0000000000001674

An advanced BLT-humanized mouse model for extended HIV-1 cure studies

Kerry J. Lavender, Craig Pace, Kathrin Sutter, Ronald J. Messer, Dakota L. Pouncey, Nathan W. Cummins, Sekar Natesampillai, Jim Zheng, Joshua Goldsmith, Marek Widera, Erik S. Van Dis, Katie Phillips, Brent Race, Ulf Dittmer, George Kukolj, Kim J. Hasenkrug

Infectious Diseases

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

Objective: Although bone marrow, liver, thymus (BLT)-humanized mice provide a robust model for HIV-1 infection and enable evaluation of cure strategies dependent on endogenous immune responses, most mice develop graft versus host disease (GVHD), limiting their utility for extended HIV cure studies. This study aimed to: evaluate the GVHD-resistant C57 black 6 (C57BL/6) recombination activating gene 2 (Rag2)-/-γ c-/-CD47-/-triple knockout (TKO)-BLT mouse as a model to establish HIV-1 latency. Determine whether TKO-BLT mice could be maintained on antiretroviral therapy (ART) for extended periods of time. Assess the rapidity of viral rebound following therapy interruption. Design: TKO-BLT mice were HIV-1 infected, treated with various ART regimens over extended periods of time and assayed for viral rebound following therapy interruption. Methods: Daily subcutaneous injection and oral ART-mediated suppression of HIV-1 infection was tested at various doses in TKO-BLT mice. Mice were monitored for suppression of viremia and cellular HIV-1 RNA and DNA prior to and following therapy interruption. Results: Mice remained healthy for 45 weeks posthumanization and could be treated with ART for up to 18 weeks. Viremia was suppressed to less than 200 copies/ml in the majority of mice with significant reductions in cellular HIV-1 RNA and DNA. Treatment interruption resulted in rapid viral recrudescence. Conclusion: HIV-1 latency can be maintained in TKO-BLT mice over extended periods on ART and rapid viral rebound occurs following therapy removal. The additional 15-18 weeks of healthy longevity compared with other BLT models provides sufficient time to examine the decay kinetics of the latent reservoir as well as observe delays in recrudescence in HIV-1 cure studies.

Original language	English (US)
Pages (from-to)	1-10
Number of pages	10
Journal	AIDS
Volume	32
Issue number	1
DOIs	https://doi.org/10.1097/QAD.0000000000001674
State	Published - Jan 2 2018

Keywords

HIV-1
antiretroviral therapy
cure
humanized mouse
latency

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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An advanced BLT-humanized mouse model for extended HIV-1 cure studies. / Lavender, Kerry J.; Pace, Craig; Sutter, Kathrin; Messer, Ronald J.; Pouncey, Dakota L.; Cummins, Nathan W.; Natesampillai, Sekar; Zheng, Jim; Goldsmith, Joshua; Widera, Marek; Van Dis, Erik S.; Phillips, Katie; Race, Brent; Dittmer, Ulf; Kukolj, George; Hasenkrug, Kim J.

In: AIDS, Vol. 32, No. 1, 02.01.2018, p. 1-10.

Research output: Contribution to journal › Article › peer-review

Lavender, Kerry J. ; Pace, Craig ; Sutter, Kathrin ; Messer, Ronald J. ; Pouncey, Dakota L. ; Cummins, Nathan W. ; Natesampillai, Sekar ; Zheng, Jim ; Goldsmith, Joshua ; Widera, Marek ; Van Dis, Erik S. ; Phillips, Katie ; Race, Brent ; Dittmer, Ulf ; Kukolj, George ; Hasenkrug, Kim J. / An advanced BLT-humanized mouse model for extended HIV-1 cure studies. In: AIDS. 2018 ; Vol. 32, No. 1. pp. 1-10.

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title = "An advanced BLT-humanized mouse model for extended HIV-1 cure studies",

abstract = "Objective: Although bone marrow, liver, thymus (BLT)-humanized mice provide a robust model for HIV-1 infection and enable evaluation of cure strategies dependent on endogenous immune responses, most mice develop graft versus host disease (GVHD), limiting their utility for extended HIV cure studies. This study aimed to: evaluate the GVHD-resistant C57 black 6 (C57BL/6) recombination activating gene 2 (Rag2)-/-γ c-/-CD47-/-triple knockout (TKO)-BLT mouse as a model to establish HIV-1 latency. Determine whether TKO-BLT mice could be maintained on antiretroviral therapy (ART) for extended periods of time. Assess the rapidity of viral rebound following therapy interruption. Design: TKO-BLT mice were HIV-1 infected, treated with various ART regimens over extended periods of time and assayed for viral rebound following therapy interruption. Methods: Daily subcutaneous injection and oral ART-mediated suppression of HIV-1 infection was tested at various doses in TKO-BLT mice. Mice were monitored for suppression of viremia and cellular HIV-1 RNA and DNA prior to and following therapy interruption. Results: Mice remained healthy for 45 weeks posthumanization and could be treated with ART for up to 18 weeks. Viremia was suppressed to less than 200 copies/ml in the majority of mice with significant reductions in cellular HIV-1 RNA and DNA. Treatment interruption resulted in rapid viral recrudescence. Conclusion: HIV-1 latency can be maintained in TKO-BLT mice over extended periods on ART and rapid viral rebound occurs following therapy removal. The additional 15-18 weeks of healthy longevity compared with other BLT models provides sufficient time to examine the decay kinetics of the latent reservoir as well as observe delays in recrudescence in HIV-1 cure studies.",

keywords = "HIV-1, antiretroviral therapy, cure, humanized mouse, latency",

author = "Lavender, {Kerry J.} and Craig Pace and Kathrin Sutter and Messer, {Ronald J.} and Pouncey, {Dakota L.} and Cummins, {Nathan W.} and Sekar Natesampillai and Jim Zheng and Joshua Goldsmith and Marek Widera and {Van Dis}, {Erik S.} and Katie Phillips and Brent Race and Ulf Dittmer and George Kukolj and Hasenkrug, {Kim J.}",

note = "Funding Information: Support for this work was provided by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institute of Health, USA, by the Mayo Clinic, by Gilead Sciences. and the Deutsche Forschungsgemeinschaft, project TRR60.",

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doi = "10.1097/QAD.0000000000001674",

language = "English (US)",

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T1 - An advanced BLT-humanized mouse model for extended HIV-1 cure studies

AU - Lavender, Kerry J.

AU - Pace, Craig

AU - Sutter, Kathrin

AU - Messer, Ronald J.

AU - Pouncey, Dakota L.

AU - Cummins, Nathan W.

AU - Natesampillai, Sekar

AU - Zheng, Jim

AU - Goldsmith, Joshua

AU - Widera, Marek

AU - Van Dis, Erik S.

AU - Phillips, Katie

AU - Race, Brent

AU - Dittmer, Ulf

AU - Kukolj, George

AU - Hasenkrug, Kim J.

N1 - Funding Information: Support for this work was provided by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institute of Health, USA, by the Mayo Clinic, by Gilead Sciences. and the Deutsche Forschungsgemeinschaft, project TRR60.

PY - 2018/1/2

Y1 - 2018/1/2

N2 - Objective: Although bone marrow, liver, thymus (BLT)-humanized mice provide a robust model for HIV-1 infection and enable evaluation of cure strategies dependent on endogenous immune responses, most mice develop graft versus host disease (GVHD), limiting their utility for extended HIV cure studies. This study aimed to: evaluate the GVHD-resistant C57 black 6 (C57BL/6) recombination activating gene 2 (Rag2)-/-γ c-/-CD47-/-triple knockout (TKO)-BLT mouse as a model to establish HIV-1 latency. Determine whether TKO-BLT mice could be maintained on antiretroviral therapy (ART) for extended periods of time. Assess the rapidity of viral rebound following therapy interruption. Design: TKO-BLT mice were HIV-1 infected, treated with various ART regimens over extended periods of time and assayed for viral rebound following therapy interruption. Methods: Daily subcutaneous injection and oral ART-mediated suppression of HIV-1 infection was tested at various doses in TKO-BLT mice. Mice were monitored for suppression of viremia and cellular HIV-1 RNA and DNA prior to and following therapy interruption. Results: Mice remained healthy for 45 weeks posthumanization and could be treated with ART for up to 18 weeks. Viremia was suppressed to less than 200 copies/ml in the majority of mice with significant reductions in cellular HIV-1 RNA and DNA. Treatment interruption resulted in rapid viral recrudescence. Conclusion: HIV-1 latency can be maintained in TKO-BLT mice over extended periods on ART and rapid viral rebound occurs following therapy removal. The additional 15-18 weeks of healthy longevity compared with other BLT models provides sufficient time to examine the decay kinetics of the latent reservoir as well as observe delays in recrudescence in HIV-1 cure studies.

AB - Objective: Although bone marrow, liver, thymus (BLT)-humanized mice provide a robust model for HIV-1 infection and enable evaluation of cure strategies dependent on endogenous immune responses, most mice develop graft versus host disease (GVHD), limiting their utility for extended HIV cure studies. This study aimed to: evaluate the GVHD-resistant C57 black 6 (C57BL/6) recombination activating gene 2 (Rag2)-/-γ c-/-CD47-/-triple knockout (TKO)-BLT mouse as a model to establish HIV-1 latency. Determine whether TKO-BLT mice could be maintained on antiretroviral therapy (ART) for extended periods of time. Assess the rapidity of viral rebound following therapy interruption. Design: TKO-BLT mice were HIV-1 infected, treated with various ART regimens over extended periods of time and assayed for viral rebound following therapy interruption. Methods: Daily subcutaneous injection and oral ART-mediated suppression of HIV-1 infection was tested at various doses in TKO-BLT mice. Mice were monitored for suppression of viremia and cellular HIV-1 RNA and DNA prior to and following therapy interruption. Results: Mice remained healthy for 45 weeks posthumanization and could be treated with ART for up to 18 weeks. Viremia was suppressed to less than 200 copies/ml in the majority of mice with significant reductions in cellular HIV-1 RNA and DNA. Treatment interruption resulted in rapid viral recrudescence. Conclusion: HIV-1 latency can be maintained in TKO-BLT mice over extended periods on ART and rapid viral rebound occurs following therapy removal. The additional 15-18 weeks of healthy longevity compared with other BLT models provides sufficient time to examine the decay kinetics of the latent reservoir as well as observe delays in recrudescence in HIV-1 cure studies.

KW - HIV-1

KW - antiretroviral therapy

KW - cure

KW - humanized mouse

KW - latency

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