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

Area of Science:

• Immunology
• Virology
• Genetics

Background:

• Bone marrow, liver, thymus (BLT)-humanized mice are crucial for HIV-1 research.
• Graft versus host disease (GVHD) in traditional BLT models limits long-term studies.
• A GVHD-resistant model is needed to advance HIV cure research.

Purpose of the Study:

• To evaluate the GVHD-resistant C57BL/6 recombination activating gene 2 (Rag2)γcCD47 triple knockout (TKO)-BLT mouse for establishing HIV-1 latency.
• To determine if TKO-BLT mice can be maintained on antiretroviral therapy (ART) for extended periods.
• To assess the speed of viral rebound after ART interruption in this model.

Main Methods:

• HIV-1 infected TKO-BLT mice were treated with various ART regimens.
• ART involved daily subcutaneous injections and oral administration at different doses.
• Mice were monitored for viral load, cellular HIV-1 RNA, and DNA suppression and rebound.

Main Results:

• TKO-BLT mice remained healthy for up to 45 weeks post-humanization.
• ART treatment was effective for up to 18 weeks, suppressing viremia below 200 copies/ml.
• Viral rebound was rapid upon ART interruption, with significant reductions in cellular HIV-1 RNA and DNA.

Conclusions:

• HIV-1 latency can be established and maintained in TKO-BLT mice for extended periods under ART.
• The extended healthspan of TKO-BLT mice (15-18 weeks longer than other BLT models) is sufficient for studying latent reservoir decay kinetics.
• This model facilitates research into HIV cure strategies by allowing observation of delayed viral recrudescence after therapy removal.