Humanized Mice Recapitulate Key Features of HIV-1 Infection: A Novel Concept Using Long-Acting Anti-Retroviral Drugs for Treating HIV-1

Abstract

Background Humanized mice generate a lymphoid system of human origin subsequent to transplantation of human CD34+ cells and thus are highly susceptible to HIV infection. Here we examined the efficacy of antiretroviral treatment (ART) when added to food pellets, and of long-acting (LA) antiretroviral compounds, either as monotherapy or in combination. These studies shall be inspiring for establishing a gold standard of ART, which is easy to administer and well supported by the mice, and for subsequent studies such as latency. Furthermore, they should disclose whether viral breakthrough and emergence of resistance occurs similar as in HIV-infected patients when ART is insufficient. Methods/Principal Findings NOD/shi-scid/γ c null (NOG) mice were used in all experimentations. We first performed pharmacokinetic studies of the drugs used, either added to food pellets (AZT, TDF, 3TC, RTV) or in a LA formulation that permitted once weekly subcutaneous administration (TMC278: non-nucleoside reverse transcriptase inhibitor, TMC181: protease inhibitor). A combination of 3TC, TDF and TMC278-LA or 3TC, TDF, TMC278-LA and TMC181-LA suppressed the viral load to undetectable levels in 15/19 (79%) and 14/14 (100%) mice, respectively. In successfully treated mice, subsequent monotherapy with TMC278-LA resulted in viral breakthrough; in contrast, the two LA compounds together prevented viral breakthrough. Resistance mutations matched the mutations most commonly observed in HIV patients failing therapy. Importantly, viral rebound after interruption of ART, presence of HIV DNA in successfully treated mice and in vitro reactivation of early HIV transcripts point to an existing latent HIV reservoir. Conclusions/Significance This report is a unique description of multiple aspects of HIV infection in humanized mice that comprised efficacy testing of various treatment regimens, including LA compounds, resistance mutation analysis as well as viral rebound after treatment interruption. Humanized mice will be highly valuable for exploring the antiviral potency of new compounds or compounds targeting the latent HIV reservoir.

Lentivector Knockdown of CCR5 in Hematopoietic Stem and Progenitor Cells Confers Functional and Persistent HIV-1 Resistance in Humanized Mice

“…NOD.scid.IL2R Ϫ/Ϫ (NSG) mice were bred and maintained in individual ventilated cages and were fed autoclaved food and water. Mice with a human immune system (humanized [hu] mice) were generated as described previously (32). Briefly, newborn (Ͻ5 days old) NSG mice received sublethal (1 Gy) total-body irradiation with a Cs source and then received 2 ϫ 10 5 transduced or untransduced CD34…”

Visualization and quantification of simian immunodeficiency virus-infected cells using non-invasive molecular imaging

“…4d). Based on these findings, establishing a non-invasive BLI for HIV-1 infection in small animals, such as humanized mice, would be useful for evaluating the effectiveness of antiviral regimes, identifying anatomical and pharmacological sanctuaries in association with persistent HIV-1 replication (Fletcher et al, 2014), and isolating drug-resistant variants (Nischang et al, 2012).…”

Differential Dynamics of HIV Infection in Humanized MISTRG versus MITRG Mice

“…We also compared the HIV-replication rate of MISTRG/ MITRG mice with other humanized mouse models that we used over the years (26,35,64,65). Advantageously, we have been using the identical infection procedure and even the same R5-tropic HIV strain, YU-2.…”