An Efficient Humanized Mouse Model for Oral Anti-Retroviral Administration

Abstract

HIV anti-retrovirals (ARVs) have vastly improved the life expectancy of people living with HIV (PLWH). However, toxic effects attributed to long-term ARV use also contribute to HIV-related co-morbidities such as heart disease, bone loss and HIV-associated neurocognitive disorders (HAND). Unfortunately, mouse models used to study the effects of ARVs on viral suppression, toxicity and HIV latency/tissue reservoirs have not been widely established. Here, we demonstrate an effective mouse model utilizing immune-compromised mice, reconstituted with infected human peripheral blood mononuclear cell (PBMCs). ARV is incorporated into mouse chow and administered daily. Combination ARV regimens included Atripla (efavirenz, tenofovir disoproxil fumarate, and emtricitabine) and Triumeq (abacavir, dolutegravir and lamivudine). Our model measures HIV-infected human cell trafficking, and ARV penetration throughout most relevant HIV organs and plasma, with a large amount of trafficking to the secondary lymphoid organs. Furthermore, te HIV viral load within each organ and the plasma was reduced in ARVs treated vs. untreated control. Overall, we have demonstrated a mouse model that is relatively easy and affordable to establish and utilize to study ARVs’ effect on various tissues, including the co-morbid conditions associated with PLWH, such as HAND, and other toxic effects.

The anti-HIV drug abacavir stimulates β-catenin activity in osteoblast lineage cells

“…We have previously measured biodistribution of orally administered ARVs in an HIV-infected mouse model, but skeletal accumulation was not evaluated. ( 30 ) Mice received control chow, TDF, monotherapy, or ABC/DTG/3TC, for 4 weeks ( n = 4, 7, 7 for control, TDF, and ABC/DTG/3TC, respectively). In the second experiment, mice received daily oral administration of control chow, TDF monotherapy, or ABC/DTG/3TC, cART for 6 weeks ( n = 10 per group).…”