In a recent study using humanized mice (mice that have received implants of human cells and tissues so that they can be infected with HIV-1), researchers tested the vaginal HIV-1 prevention efficacy of single and combination antiviral compounds applied locally. They used a mathematical model to empirically study the effects of administering different doses of antiviral drugs. The results were unexpected: when tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) – both drugs that share the same mechanism of inhibiting HIV-1 reverse transcriptase thereby preventing viral replication in immune cells – were combined with a third drug that used a different mode of action against HIV-1, a strong antagonistic effect was observed. This means that the drugs were less effective when used together than they were when used separately. The TDF-FTC combination is FDA-approved as an oral regimen to prevent the acquisition of HIV-1.

The researchers were able to remedy the antagonistic effect by omitting TDF from the drug regimen. The management of HIV-1 in infected individuals using antiretroviral therapy relies on two or more drugs administered together to suppress the virus. It was hypothesized by many in the field that a similar paradigm would apply to HIV-1 prevention in healthy individuals. The results of this new study suggest that the approaches used in treatment may not be directly transferrable to HIV-1 prevention, especially in topical (i.e., vaginal) dosing.

Vaginal HIV-1 prevention efficacy in BLT hu-mice increased when TDF was omitted

This study provides a translational template for the preclinical evaluation of drug combinations for the prevention of HIV-1 and other viral diseases. Mice and humans have different physiology and microenvironments in their vaginal tissues, and those differences may limit the translational potential of these study results in humans. It is an important step forward in the development of safe, effective, and discreet HIV prevention products that can be controlled by women. The senior author on the report, Dr. Marc Baum at Oak Crest Institute of Science admits that the findings are "..going to be a bit controversial. The interaction between drugs that are effective when used alone but may interfere with each other when combined highlights the complexity of predicting the effects of drug use in HIV prevention. This serves as a reminder that more is not always better."

Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, under Award Number U19AI113048. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Reference to paper
https://www.nature.com/articles/s41598-023-31695-5
https://pubmed.ncbi.nlm.nih.gov/36944714/

Humanized Mice

A humanized mouse is a type of laboratory mouse that has been genetically modified so that it has certain human characteristics. For this study, the mice were implanted with human immune cells and tissues so that they could be infected with HIV-1

Humanized mice are a powerful tool in biomedical research, helping scientists to better understand human biology and develop new treatments for diseases.