Novel preclinical models of topical PrEP pharmacodynamics provide rationale for combination of drugs with complementary properties

Retrovirology

Betsy C Herold⁵  Patrick F Kiser²  James M Smith⁴  Robert W Buckheit Jr³  Karen W Buckheit³  Michael S Kay¹  Tammy Evans-Strickfaden⁴  Rachna Rastogi²  Todd J Johnson²  Priya Srinivasan⁴  Pedro MM Mesquita⁵ 

[1] Department of Biochemistry, University of Utah, Salt Lake City, UT, USA;Department of Bioengineering, University of Utah, Salt Lake City, UT, USA;ImQuest BioSciences Inc, Frederick, MD, USA;Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA;Departments of Pediatrics and Microbiology &Immunology, Albert Einstein College of Medicine, Bronx, NY, USA

关键词: Preclinical models;    Microbicide;    Intravaginal ring;    Pre-Exposure Prophylaxis;    HIV;   

Others  :  806976
DOI  :  10.1186/1742-4690-10-113

 received in 2013-07-19, accepted in 2013-10-02,  发布年份 2013

【 摘 要 】

Background

The limited success of recent HIV topical pre-exposure prophylaxis clinical trials highlights the need for more predictive models of drug efficacy that better simulate what may happen during sexual exposure. To address this gap, we developed complementary in vitro models to evaluate the ability of drugs to retain anti-HIV activity if cells were washed with seminal plasma (simulating what may happen following exposure to ejaculate), and to protect drug-naive T cells (representing newly recruited immune cells) co-cultured with explants that had been pretreated with drug. We focused on tenofovir disoproxil fumarate (TDF), the non-nucleoside reverse transcriptase inhibitors dapivirine (DPV) and IQP-0528, and the entry inhibitors maraviroc (MVC) and the D-peptide chol-PIE-12 trimer (PIE12). Studies were extended to macaques and the ability of cervical biopsies obtained from animals treated with an intravaginal ring formulation of IQP-0528 to protect ex vivo co-cultured T cells was determined. The antiviral activity of cervicovaginal lavage samples against a primary Clade C isolate was also measured and correlated with drug levels.

Results

Cells exposed to TDF were equally protected from HIV whether or not the drug-treated cells were washed with medium or seminal plasma prior to challenge. In contrast, several-fold higher concentrations of NNRTIs and entry inhibitors were needed to attain similar levels of HIV inhibition following a wash with seminal plasma. Conversely, the NNRTIs and PIE12, but not TDF or MVC, were effectively transferred from ex vivo treated explants and protected co-cultured T cells. Biopsies obtained from IQP-0528 ring-treated macaques also protected co-cultured T cells with viral inhibition ranging from 42-72%. Antiviral activity correlated with the concentration of drug recovered. Combinations of TDF with IQP-0528 protected in both in vitro models.

Conclusions

Together, these models suggest that intracellularly retained drugs such as TDF may protect resident immune cells following coitus but sustained delivery may be required to protect immune cells subsequently recruited into the genital tract. Sustained delivery may also be critical for NNRTIs, which are rapidly transported out of cells and could be lost following sexual intercourse. An ideal approach may be a combination of drugs with complementary bioavailability profiles formulated for sustained delivery.

【 授权许可】

   
2013 Mesquita et al.; licensee BioMed Central Ltd.

【 图 表 】

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