# Pharmacological evaluation of an ex vivo cervicovaginal HIV prevention model

## TL;DR

This study evaluates how well a lab model of cervical tissue can predict the effectiveness of HIV prevention drugs in different parts of the female genital tract.

## Contribution

The study introduces a model to assess regional variability in drug efficacy for HIV prevention in the female genital tract.

## Key findings

- Differences in drug-metabolizing enzyme expression were found between ecto- and endocervical tissues.
- Tenofovir diphosphate levels were linked to reduced viral replication in ectocervical tissues.
- Ectocervical explants showed consistent viral infectivity and dose-dependent drug inhibition.

## Abstract

The female genital tract (FGT) is a unique compartment with physiologically distinct properties complicating the extrapolation of drug efficacy; critical gaps remain in understanding regional variability within the FGT itself. We performed an in-depth investigation across endo- and ectocervical tissues on the utility of the cervical explant model to evaluate pre-exposure prophylaxis (PrEP) efficacy.

Using normal cervical tissues, we evaluated gene expression of relevant drug metabolizing enzymes and transporters (DMETs) via qRT-PCR and compared ecto- and endocervix. To determine differences in drug phosphorylation and to assess antiretroviral (ARV) efficacy, we incubated explants in tenofovir and emtricitabine then measured intracellular metabolites. Viral infectivity and dose–response with ARVs was measured using viral RNA and p24 following HIV-1JR-CSF challenge.

ABCC4 expression was 3-fold lower in ectocervical tissues compared with endocervical, whereas CYP3A5 was 2-fold higher. IL-6 was correlated with ABCB1 (r = 0.52, P = 0.01) and ABCG2 (r = 0.56, P =0.005). Dose-normalized phosphorylation did not differ between endo- and ectocervix (P > 0.5). Infectivity of explants was low (53%) but did not differ by compartment. Intracellular tenofovir diphosphate concentrations were associated with a decrease in ectocervical viral replication (r =0.39, P < 0.05). There was a strong relationship between the proportion of explants infected and emtricitabine dose (P =0.02) but no relationship between intracellular emtricitabine triphosphate and protection.

We identified differences in DMET expression and ARV metabolism between ecto- and endocervical tissues, as well as correlations between DMET and IL-6. Ectocervical explants demonstrated consistent viral infectivity and dose-dependent inhibition. The model is useful in determining tenofovir diphosphate targets.