M48U1 and Tenofovir combination synergistically inhibits HIV infection in activated PBMCs and human cervicovaginal histocultures

Giuseppina Musumeci,Gilles Ponchel,Lucia Lopalco,David Lembo,Kawthar Bouchemal,Davide Gibellini,Caterina Signoretto,Valeria Cagno,Claudia Pastori,Erica Diani,Maria Carla Re,Loïc Martin,Isabella Bon

doi:10.1038/srep41018

Abstract

Microbicides are considered a promising strategy for preventing human immunodeficiency virus (HIV-1) transmission and disease. In this report, we first analyzed the antiviral activity of the miniCD4 M48U1 peptide formulated in hydroxyethylcellulose (HEC) hydrogel in activated peripheral blood mononuclear cells (PBMCs) infected with R5- and X4–tropic HIV-1 strains. The results demonstrate that M48U1 prevented infection by several HIV-1 strains including laboratory strains, and HIV-1 subtype B and C strains isolated from the activated PBMCs of patients. M48U1 also inhibited infection by two HIV-1 transmitted/founder infectious molecular clones (pREJO.c/2864 and pTHRO.c/2626). In addition, M48U1 was administered in association with tenofovir, and these two antiretroviral drugs synergistically inhibited HIV-1 infection. In the next series of experiments, we tested M48U1 alone or in combination with tenofovir in HEC hydrogel with an organ-like structure mimicking human cervicovaginal tissue. We demonstrated a strong antiviral effect in absence of significant tissue toxicity. Together, these results indicate that co-treatment with M48U1 plus tenofovir is an effective antiviral strategy that may be used as a new topical microbicide to prevent HIV-1 transmission.

Highlights

According to World Health Organization (WHO)[1] approximately 37 million people worldwide are currently infected with HIV-1, with 2 million new cases of infection and 1.2 million deaths from AIDS-related causes per year
We studied the antiretroviral efficacy of miniCD4 M48U1 alone or in combination with tenofovir in vitro in both peripheral blood mononuclear cells (PBMCs) and cervicovaginal histocultures
Infection of activated PBMCs with R5-tropic HIV-1BaL or X4-tropic HIV-1IIIb was inhibited by treatment with HEC formulations of miniCD4 M48U1 or tenofovir

Summary

Introduction

According to World Health Organization (WHO)[1] approximately 37 million people worldwide are currently infected with HIV-1, with 2 million new cases of infection and 1.2 million deaths from AIDS-related causes per year. AIDS is the leading cause of death in women of reproductive age in this region[1,3] These data indicate the need to develop useful approaches to protect women from HIV-1 infection, especially since sexual intercourse is the principal route of HIV-1 transmission[1]. We studied the antiretroviral efficacy of miniCD4 M48U1 alone or in combination with tenofovir in vitro in both PBMCs and cervicovaginal histocultures We propose that this combination may be used as a novel microbicide for inhibiting HIV-1 transmission through sexual intercourse

Methods

Results

Conclusion