In FY 2018 we used our humanized mouse model to investigate the therapeutic effects of interferon alpha subtype 14 against HIV infection in vivo. We previously showed that human IFN-alpha14 subtype had 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 treatment of latent HIV infections. IFN-alpha14 significantly suppressed HIV-1 replication and proviral loads but did not cure infection. IFN-alpha14 therapy was associated with increased intrinsic and innate immunity, including significantly higher induction of TRAIL(+) NK cells. Andrew Badely at the Mayo Clinic has shown that HIV induces the expression of a truncated form of TRAIL, TRAIL short, that antagonizes TRAIL-mediated killing. We are now combining IFNa14 to induce TRAIL with anti-TRAIL short antibodies to see if it causes an effect on latent HIV levels. 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). We have now demonstrated that mice 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. Thus, 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. 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). Ebola virus (EBOV) and Marburg virus (MARV) outbreaks are highly lethal, and infection results in a hemorrhagic fever with complex etiology. These zoonotic viruses dysregulate the immune system to cause disease, in part by replicating within myeloid cells that would normally innately control viral infection and shape the adaptive immune response. The previous study was extended to show that triple knockout (TKO)-bone marrow, liver, thymus (BLT) humanized mice recapitulate the early in vivo human immune response to filovirus infection. Disease severity in TKO-BLT mice was dissimilar between EBOV and MARV with greater severity observed during EBOV infection. Disease severity was related to increased Kupffer cell infection in the liver, higher levels of myeloid dysfunction, and skewing of macrophage subtypes in EBOV compared with MARV-infected mice. Overall, the TKO-BLT model provided a practical in vivo platform to study the human immune response to filovirus infection and generated a better understanding of how these viruses modulate specific components of the immune system.
