title: MiniCD4 microbicide prevents HIV infection of human mucosal explants and vaginal transmission of SHIV(162P3) in cynomolgus macaques.
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-1(Ba-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 SHIV(162P3) 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 AID(50) of SHIV(162P3). All control animals were infected with a peak plasma viral load of 10(5)-10(6) 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.
authors.affiliation: CEA, Division of Immuno-Virology, iMETI, Fontenay-aux Roses, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dereuddre-Bosquet
authors.forename: Laurence
authors.initials: L
authors.lastname: Morellato-Castillo
authors.forename: Joachim
authors.initials: J
authors.lastname: Brouwers
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
authors.forename: Kawthar
authors.initials: K
authors.lastname: Bouchemal
authors.forename: Gilles
authors.initials: G
authors.lastname: Ponchel
authors.forename: Oscar H P
authors.initials: OH
authors.lastname: Ramos
authors.forename: Carolina
authors.initials: C
authors.lastname: Herrera
authors.forename: Martha
authors.initials: M
authors.lastname: Stefanidou
authors.forename: Robin
authors.initials: R
authors.lastname: Shattock
authors.forename: Leo
authors.initials: L
authors.lastname: Heyndrickx
authors.forename: Guido
authors.initials: G
authors.lastname: Vanham
authors.forename: Pascal
authors.initials: P
authors.lastname: Kessler
authors.forename: Roger
authors.initials: R
authors.lastname: Le Grand
authors.forename: Loïc
authors.initials: L
authors.lastname: Martin
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000494:pharmacology*; D005260:Female; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D057786:Peptidomimetics / Q000494:pharmacology*; D012367:RNA, Viral / Q000097:blood; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000517:prevention & control* / Q000635:transmission; D015302:Simian Immunodeficiency Virus / Q000378:metabolism* / Q000472:pathogenicity
chemical_list: D015704:CD4 Antigens; D057786:Peptidomimetics; D012367:RNA, Viral