MiniCD4 microbicide prevents HIV infection of human mucosal explants and vaginal transmission of SHIV(162P3) in cynomolgus macaques.

Nathalie Dereuddre-Bosquet,Roger Le Grand,Pascal Kessler,Gilles Ponchel,Robin Shattock,Laurence Morellato-Castillo,Martha Stefanidou,Oscar H P Ramos,Kawthar Bouchemal,Leo Heyndrickx,Loïc Martin,Carolina Herrera,Joachim Brouwers,Guido Vanham,Patrick Augustijns

doi:10.1371/journal.ppat.1003071

Abstract

In complement to an effective vaccine, development of potent anti-HIV microbicides remains an important priority. We have previously shown that the miniCD4 M48U1, a functional mimetic of sCD4 presented on a 27 amino-acid stable scaffold, inhibits a broad range of HIV-1 isolates at sub-nanomolar concentrations in cellular models. Here, we report that M48U1 inhibits efficiently HIV-1Ba-L in human mucosal explants of cervical and colorectal tissues. In vivo efficacy of M48U1 was evaluated in nonhuman primate (NHP) model of mucosal challenge with SHIV162P3 after assessing pharmacokinetics and pharmacodynamics of a miniCD4 gel formulation in sexually matured female cynomolgus macaques. Among 12 females, half were treated with hydroxyethylcellulose-based gel (control), the other half received the same gel containing 3 mg/g of M48U1, one hour before vaginal route challenge with 10 AID50 of SHIV162P3. All control animals were infected with a peak plasma viral load of 105–106 viral RNA (vRNA) copies per mL. In animals treated with miniCD4, 5 out of 6 were fully protected from acquisition of infection, as assessed by qRT-PCR for vRNA detection in plasma, qPCR for viral DNA detection in PBMC and lymph node cells. The only infected animal in this group had a delayed peak of viremia of one week. These results demonstrate that M48U1 miniCD4 acts in vivo as a potent entry inhibitor, which may be considered in microbicide developments.

Highlights

In complement to an effective vaccine against HIV transmission, development of potent anti-HIV microbicides remains important strategies to consider for HIV prevention [1,2]
This report describes the protective effect of a CD4 peptide mimetic against HIV infection on human mucosal explants and further on, when used in a microbicide gel, against a simian-human immunodeficiency virus (SHIV) challenge in cynomolgus macaques
We demonstrated that such a small CD4 mimetic peptide could represent a powerful preventive agent against sexual HIV transmission, validating miniaturized protein interface design up to the discovery of potential new drugs

Summary

Introduction

In complement to an effective vaccine against HIV transmission, development of potent anti-HIV microbicides remains important strategies to consider for HIV prevention [1,2]. The observed levels of protection were less than optimal reaching only 50% in those reporting .80% adherence to the dosing strategy. More recently trial of a once-daily dosing regimen with tenofovir gel (VOICE) failed to demonstrate any detectable efficacy in at risk women. These studies underline the need to develop additional microbicide candidates with complementary or synergistic activity. The combination of different antiretroviral candidates acting on different steps of the viral cycle and possessing non-overlapping resistance profiles might be a key to increasing the levels of protection observed in the CAPRISA-004 trial. Only few microbicide candidates, in early clinical development, have been tested for efficacy against vaginal or rectal SIV/SHIV challenge in macaques, providing proof of concept for accelerated clinical development

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Results

Conclusion