The HIV pandemic continues to spread. Even in the United States and Europe with their relative universal access to combined anti-retroviral treatment (ART), the prevalence of HIV-infected people is increasing. The 2nd and 3rd generation antivirals are very efficacious. The life expectancy of treated HIV-infected individuals has significantly improved over the last two decades and, in turn, has contributed to the increasing prevalence. However, ART has significant shortcomings, including adverse events, psychological dependence, life-long adherence and cost. Incomplete adherence results in the emergence of drug-resistant HIV strains. Novel and simpler treatment strategies and, in the best-case scenario, a cure are needed.
The HIV pandemic started with an ancestral SIV from a non-human primate crossing into humans, and thus, it is not surprising that HIV replication is limited to human and non-human primate cells. Mouse models of HIV infection have been generated by engrafting human lymphoid tissue into SCID mice and are receptive to HIV. For example, SCID mice transplanted with fetal liver (liv) and thymus (thy) tissue were very valuable for studying various aspects of HIV pathogenesis, including HIV-induced pathology in the thy/liv implant, screening anti-viral compounds and hematopoietic stem cell–based gene therapy. However, these studies are limited to the thy/liv implant.
Development of a human adaptive immune system in cord blood cell–transplanted mice renewed the interest in humanized mice (hu mice): hematopoietic CD34+ cells were preferentially transplanted into the liver of newborn mice or i.v. at older age. The mice develop a lymphoid-like system of human origin with T and B cells, monocytes, plasmacytoid and conventional DCs, thymus and lymph nodes. Their mature T cells have a broad Vβ repertoire, and more than 40% of T cells display a naive phenotype. This breakthrough was only realized through the development of heavily immunodeficient mice by crossing of SCID mice with non-obese diabetic (NOD) mice and mice deficient in the gamma c (γc) chain of the IL-2 receptor or the generation of Rag1 or 2−/− γc−/− knock-out mice.
We and others demonstrated that these hu mice are highly permissive to HIV infection when challenged with CCR5- or CXCR4-tropic HIV strains and show viral dissemination and progressive CD4+ T-cell loss.
To validate the experimental significance of hu mice for studying HIV pathogenesis and their value for novel interventional approaches, key aspects of HIV infection/pathogenesis must be fulfilled. The model should recapitulate ART of disseminated HIV infection with subsequent recovery of the immune system; interruption of ART should result in a rebound of HIV replication from the latent reservoir. Five studies reported the effects of ART in HIV-infected humanized mice using different drugs and drug combinations. While these reports are very promising that humanized mice may be the long awaited small animal model for preclinical proof-of-concept studies, they lack pharmacokinetic (PK) studies for the medicinal compounds used except for the report by Choudhary et al that would help to compare the data obtained in humanized mice to a clinical context.
A “standardized" ART scheme that completely suppresses HIV RNA replication in hu mice would be highly valuable for pre-clinical proof-of-concept studies for novel anti-retroviral compounds and studies of latency that closely approximate the situation in HIV-infected humans treated with ART.
Thus, we sought to determine if this mouse model is valuable for studying antiretroviral treatment of disseminated HIV infection and if it recapitulates key features, such as viral rebound, break-through replication and viral rebound subsequent to interruption of ART. We made a major effort to define the dose of antiretroviral compounds added to the food pellets to compare data to human studies. We also benefited from access to antiretroviral compounds in special formulation that permit once weekly dosing in mice. Thus, we also were able to study a novel concept of anti-HIV therapy based on LA antiretroviral drugs.