In FY 2017 we used our humanized mouse model to investigate the therapeutic effects of 12 different subtypes of interferon alpha against HIV infection in vitro and in vivo. Although all 12 subtypes of human interferon alpha (IFN-alpha) bind the same receptor, we found that the human IFN-alpha14 subtype had the most potent anti-HIV activity, and was much stronger than the IFN-alpha2 subtype, which is currently in HIV-1 clinical trials. We used our TKO_BLT-humanized mouse model to test the efficacy of IFN-alpha14 in both postexposure prophylaxis and treatment of acute infections. IFN-alpha14, but not IFN-alpha2, significantly suppressed HIV-1 replication and proviral loads. Successful IFN-alpha14 therapy was associated with increased intrinsic and innate immunity, including significantly higher induction of tetherin and MX2, increased APOBEC3G signature mutations in HIV-1 proviral DNA, and higher frequencies of TRAIL(+) NK cells. This discovery identifies IFN-alpha14 as a more powerful IFN-alpha subtype for use in combination therapy trials aimed toward an HIV cure (Lavender et al. Journal of Virology 2016). The TKO-BLT-humanized mouse developed in our lab was shown to have a much longer healthy survival time than other humanized mouse models, which typically develop graft vs host disease after only a few months of human cell and tissue engraftment. We showed that TKO-BLT mice survive for at least 45 weeks post-infection with HIV. This unique aspect of the model makes it a tenable mouse model for studying HIV cure therapies that required long time periods under antiretroviral therapy followed by therapeutic strategies to re-activate latent infections and kill infected cells (Akkina et al. AIDS Research and Human Retroviruses 2016). In a collaboration with Joseph Prescott in the Laboratory of Virology, we tested the ability of TKO-BLT mice to support infection with Ebola virus. The mice were successfully infected with Ebola and are being developed for use in pathogenesis studies, immunological studies, and therapeutic screening (Spengler et al. Journal of Infectious Diseases 2017).

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7
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2017
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Lavender, Kerry J; Williamson, Brandi N; Saturday, Greg et al. (2018) Pathogenicity of Ebola and Marburg Viruses Is Associated With Differential Activation of the Myeloid Compartment in Humanized Triple Knockout-Bone Marrow, Liver, and Thymus Mice. J Infect Dis :
Hasenkrug, Kim J; Chougnet, Claire A; Dittmer, Ulf (2018) Regulatory T cells in retroviral infections. PLoS Pathog 14:e1006776
Lavender, Kerry J; Pace, Craig; Sutter, Kathrin et al. (2018) An advanced BLT-humanized mouse model for extended HIV-1 cure studies. AIDS 32:1-10
Lavender, Kerry J; Gibbert, Kathrin; Peterson, Karin E et al. (2016) Interferon Alpha Subtype-Specific Suppression of HIV-1 Infection In Vivo. J Virol 90:6001-6013
Akkina, Ramesh; Allam, Atef; Balazs, Alejandro B et al. (2016) Improvements and Limitations of Humanized Mouse Models for HIV Research: NIH/NIAID ""Meet the Experts"" 2015 Workshop Summary. AIDS Res Hum Retroviruses 32:109-19
Van Dis, Erik S; Moore, Tyler C; Lavender, Kerry J et al. (2016) No SEVI-mediated enhancement of rectal HIV-1 transmission of HIV-1 in two humanized mouse cohorts. Virology 488:88-95
Harper, Michael S; Guo, Kejun; Gibbert, Kathrin et al. (2015) Interferon-? Subtypes in an Ex Vivo Model of Acute HIV-1 Infection: Expression, Potency and Effector Mechanisms. PLoS Pathog 11:e1005254
Lavender, Kerry J; Pang, Wendy W; Messer, Ronald J et al. (2013) BLT-humanized C57BL/6 Rag2-/-?c-/-CD47-/- mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection. Blood 122:4013-20