A dual-purpose hu-mouse model for evaluating SIV and HIV cure strategies

项目总结/文摘:

Project Summary/Abstract: Due to their proven track record in HIV research, NHPs will continue to play a major role into the foreseeable future in HIV cure research. However, the wider use of NHPs is somewhat restrictive due to their high cost and limited supply. In this regard, a small animal model that can serve as a preliminary in vivo screen for the initial evaluation of promising, in vitro-tested, new drugs prior to their evaluation in SIV infected NHPs would be of great benefit in saving time, and in helping to formulate more informed studies. If this same animal model could also allow for the testing of drugs against HIV directly, it would serve two major purposes i. e., the simultaneous ability to test drugs active against both HIV and SIV. In our ongoing work on SIV progenitor viral evolution into HIV, we discovered that humanized mice (hu-mice) transplanted with a human immune system are susceptible to SIVs, namely SIV-chimpanzee (SIVcpz) and SIV-sooty mangabey (SIVsm) that gave rise to HIV-1 and HIV-2, respectively. This forms a basis for our proposed work here to develop and investigate a versatile small animal model that can facilitate the testing of anti-HIV and/or anti-SIV drugs as well as broadly neutralizing antibodies (bNAbs). If successful, this will be a unique model that would benefit both the HIV and SIV research groups involved in cure strategies to streamline their testing pipelines more effectively using the same drugs or biologics on two different viruses within the same animal model. Our specific aims are: Aim 1: Evaluate the humanized mouse model for productive and chronic infection with frequently used SIVs and SHIVs in AIDS research such as SIVmac251, SHIVSF162P3 and RT-SHIV. Aim 2: Validate the utility of the hu-mouse model for in vivo efficacy testing of new generation ARV drugs against SIV and SHIV viruses, namely, NRTI Tenofovir alafenamide (TAF), Islatravir, (4'-ethynyl-2-fluoro-2’- deoxyadenosine, EFdA), Cabotegravir (CAB), and Lenacapvir (GS-6207) Aim 3: Investigate the hu-mouse model for in vivo efficacy testing of bNAbs against SIV and SHIV viruses: Here will evaluate select HIV bNAbs 10-1074 and 3BNC117 on SHIV viruses and bNAbs against SIV ITS103.01 and ITS90.03 in the hu-mouse system Aim 4: Evaluate viral latency reversal and potential cure strategies on SIV/SHIV viruses in the hu-mouse model system: A select combinatorial approaches that incorporate ARVs, LRAs, TLR agonists, and bNAbs against SIV and SHIV to validate the utility of hu-mice in HIV/SIV cure research.