Mice cannot be used as a model to evaluate HIV-1
therapeutics because they do not become infected by HIV-1 due to structural differences between several human and mouse
proteins required for HIV-1 replication. This has limited their use for in vivo assessment of anti-HIV-1
therapeutics and the mechanism by which cofactors, such as
illicit drug use accelerate HIV-1 replication and disease course in substance abusers. Here, we describe the development and application of two in vivo humanized mouse models that are highly sensitive and useful models for the in vivo evaluation of candidate anti-HIV
therapeutics. The first model, hu-spl-PBMC-NSG mice, uses NOD-SCID IL2rγ(-/-) (NSG) mice intrasplenically injected with human peripheral blood mononuclear cells (PBMC) which develop productive splenic HIV-1
infection after intrasplenic inoculation with a replication-competent HIV-1 expressing Renilla reniformis
luciferase (HIV-LucR) and enables investigators to use bioluminescence to visualize and quantitate the temporal effects of
therapeutics on HIV-1
infection. The second model, hCD4/R5/cT1 mice, consists of transgenic mice carrying human CD4, CCR5 and
cyclin T1 genes, which enables murine CD4-expressing cells to support HIV-1 entry, Tat-mediated LTR transcription and consequently develop productive
infection. The hCD4/R5/cT1 mice develop disseminated
infection of tissues including the spleen, small intestine, lymph nodes and lungs after
intravenous injection with HIV-1-LucR. Because these mice can be infected with HIV-LucR expressing transmitted/founder and clade A/E and C Envs, these mouse models can also be used to evaluate the in vivo efficacy of
broadly neutralizing antibodies and
antibodies induced by candidate HIV-1
vaccines. Furthermore, because hCD4/R5/cT1 mice can be infected by vaginal inoculation with replication-competent HIV-1 expressing
NanoLuc (HIV-nLucR)-, this mouse model can be used to evaluate the mechanisms by which
substance abuse and other factors enhance mucosal transmission of HIV-1.