MiniCD4 Microbicide Prevents HIV Infection of Human Mucosal Explants and Vaginal Transmission of SHIV162P3 in Cynomolgus Macaques

PLoS Pathogens

Loïc Martin¹  Nathalie Dereuddre-Bosquet¹  Joachim Brouwers²  Roger Le Grand²  Carolina Herrera²  Robin Shattock³  Pascal Kessler⁴  Guido Vanham⁴  Kawthar Bouchemal⁵  Patrick Augustijns⁵  Gilles Ponchel⁶  Oscar H. P. Ramos⁶  Laurence Morellato-Castillo⁷  Leo Heyndrickx⁸  Martha Stefanidou⁸ 

[1] CEA, Division of Immuno-Virology, iMETI, Fontenay-aux Roses, France;CEA, iBiTecS, Service d'Ingénierie Moléculaire des Protéines, Gif sur Yvette, France;Department of Pediatrics and Microbiology-Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America;Institute of Tropical Medicine and University of Antwerp, Antwerp, Belgium;Katholieke Universiteit Leuven, Leuven, Belgium;Paris-Sud University, Faculty of Pharmacy, Chatenay-Malabry, France;Paris-Sud University, UMRE01, Orsay, France;Section of Infectious Diseases, Faculty of Medicine, St Mary's Campus, Imperial College, London, United Kingdom

关键词: Macaque;    Microbicides;    Blood plasma;    T cells;    HIV-1;    Pharmacokinetics;    HIV;    Viremia;   

DOI  :  10.1371/journal.ppat.1003071

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY