Highly synergistic drug combination prevents vaginal HIV infection in humanized mice

Baum, Marc M.; Ramirez, Christina M.; Moss, John A.; Gunawardana, Manjula; Bobardt, Michael; Gallay, Philippe

doi:10.1038/s41598-020-69937-5

Cited by 3 publications

(14 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The BLT hu-mouse model has been used extensively in efficacy studies involving HIV-1 prevention research 54 – 58 . Here, oral TAF formulations of varying drug concentrations were administered to BLT hu-mice via gavage.…”

Section: Resultsmentioning

confidence: 99%

“…The generation of BLT hu-mice was performed as described in Baum et al 58 , and the references contained therein.…”

Section: Methodsmentioning

confidence: 99%

“…Efficacy studies were performed by administering BLT hu-mice ( N = 8 per dosing group; 5 dosing groups per arm; two arms; 80 mice total) a freshly prepared TAF (0.35, 0.50, 0.75, 1.00, or 2.00 mg corresponding to 0.73, 1.05, 1.57, 2.10, and 4.20 µmol) solution in 50 mM citric acid (pH 5.0) via oral gavage. Vaginal or rectal challenge with HIV-1 was performed 6 h after dosing and HIV-1 infection status was monitored by quantifying viral RNA concentration in peripheral blood (plasma) at 1, 2, 3, 6, and 12 weeks post challenge as fully described in Baum et al 58 , and the references contained therein.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Fundamental aspects of long-acting tenofovir alafenamide delivery from subdermal implants for HIV prophylaxis

Gunawardana

Remedios-Chan

Sanchez

et al. 2022

Sci Rep

Self Cite

View full text Add to dashboard Cite

Global efforts aimed at preventing human immunodeficiency virus type one (HIV-1) infection in vulnerable populations appear to be stalling, limiting our ability to control the epidemic. Long-acting, controlled drug administration from subdermal implants holds significant potential by reducing the compliance burden associated with frequent dosing. We, and others, are exploring the development of complementary subdermal implant technologies delivering the potent prodrug, tenofovir alafenamide (TAF). The current report addresses knowledge gaps in the preclinical pharmacology of long-acting, subdermal TAF delivery using several mouse models. Systemic drug disposition during TAF implant dosing was explained by a multi-compartment pharmacokinetic (PK) model. Imaging mass spectrometry was employed to characterize the spatial distribution of TAF and its principal five metabolites in local tissues surrounding the implant. Humanized mouse studies determined the effective TAF dose for preventing vaginal and rectal HIV-1 acquisition. Our results represent an important step in the development of a safe and effective TAF implant for HIV-1 prevention.

show abstract

Section: Resultsmentioning

confidence: 99%

“…The generation of BLT hu-mice was performed as described in Baum et al 58 , and the references contained therein.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Fundamental aspects of long-acting tenofovir alafenamide delivery from subdermal implants for HIV prophylaxis

Gunawardana

Remedios-Chan

Sanchez

et al. 2022

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…In contrast, humanized mice contain human CD4+ T cells, which are permissible to HIV-1 infection and simultaneously allow in-depth analysis of the human immune response to HIV-1 pathogenesis in vivo . Humanized mice have provided important insights into preventative approaches to HIV-1 infection ( 6 – 8 ). These approaches have been reviewed in detail elsewhere ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

Humanized Mice for the Evaluation of Novel HIV-1 Therapies

Abeynaike

Paust

2021

Front. Immunol.

View full text Add to dashboard Cite

With the discovery of antiretroviral therapy, HIV-1 infection has transitioned into a manageable but chronic illness, which requires lifelong treatment. Nevertheless, complete eradication of the virus has still eluded us. This is partly due to the virus’s ability to remain in a dormant state in tissue reservoirs, ‘hidden’ from the host’s immune system. Also, the high mutation rate of HIV-1 results in escape mutations in response to many therapeutics. Regardless, the development of novel cures for HIV-1 continues to move forward with a range of approaches from immunotherapy to gene editing. However, to evaluate in vivo pathogenesis and the efficacy and safety of therapeutic approaches, a suitable animal model is necessary. To this end, the humanized mouse was developed by McCune in 1988 and has continued to be improved on over the past 30 years. Here, we review the variety of humanized mouse models that have been utilized through the years and describe their specific contribution in translating HIV-1 cure strategies to the clinic.

show abstract

“…Either 8 or 10 mice per group were employed. The statistical power resulting from these group sizes was calculated using two-sided binomial tests, and has been reported previously 27 . Viral RNA was measured in plasma at 1, 2, 3, 6, and 12 weeks post challenge to determine if infection occurred.…”

Section: Resultsmentioning

confidence: 99%

Acute antagonism in three-drug combinations for vaginal HIV prevention in humanized mice

Gallay

Ramirez

Baum

2023

Sci Rep

Self Cite

View full text Add to dashboard Cite

Adolescent girls and young women in low- to middle-income countries are disproportionately at risk of becoming HIV-1 infected. New non-vaccine biomedical products aimed at overcoming this global health challenge need to provide a range of safe, effective, and discreet dosage forms based on the delivery of one or more antiviral compounds. An overarching strategy involves vaginal drug administration through inserts/tablets, gels, films, and intravaginal rings. The approach derives its appeal from being women-controlled and topical, there-by potentially minimizing systemic exposure to the agents and their metabolites. Oral regimens based on tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are established and effective in HIV-1 pre-exposure prophylaxis (PrEP), and form a promising basis for vaginal PrEP. Here, we used bone marrow/liver/thymus humanized mice to measure the in vivo efficacy against HIV-1 of single and combination antiviral compounds applied vaginally, coupled with data analysis using the Chou-Talalay mathematical model to study the dose–effect characteristics. Unexpectedly, strong antagonism was observed in drug combinations composed of TDF-FTC coupled with a third agent using a different mode of action against HIV-1. The antagonistic effect was remedied when TDF was omitted from the regimen. Our approach provides a translational template for the preclinical, rational, and systematic evaluation of drug combinations for the prevention of HIV-1, and other viral diseases.

show abstract

Highly synergistic drug combination prevents vaginal HIV infection in humanized mice

Cited by 3 publications

References 40 publications

Fundamental aspects of long-acting tenofovir alafenamide delivery from subdermal implants for HIV prophylaxis

Fundamental aspects of long-acting tenofovir alafenamide delivery from subdermal implants for HIV prophylaxis

Humanized Mice for the Evaluation of Novel HIV-1 Therapies

Acute antagonism in three-drug combinations for vaginal HIV prevention in humanized mice

Contact Info

Product

Resources

About