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CD4-mimetic sulfopeptide conjugates display sub-nanomolar anti-HIV-1 activity and protect macaques against a SHIV162P3 vaginal challenge.

ABSTRACT: The CD4 and the cryptic coreceptor binding sites of the HIV-1 envelope glycoprotein are key to viral attachment and entry. We developed new molecules comprising a CD4 mimetic peptide linked to anionic compounds (mCD4.1-HS12 and mCD4.1-PS1), that block the CD4-gp120 interaction and simultaneously induce the exposure of the cryptic coreceptor binding site, rendering it accessible to HS12- or PS1- mediated inhibition. Using a cynomolgus macaque model of vaginal challenge with SHIV162P3, we report that mCD4.1-PS1, formulated into a hydroxyethyl-cellulose gel provides 83% protection (5/6 animals). We next engineered the mCD4 moiety of the compound, giving rise to mCD4.2 and mCD4.3 that, when conjugated to PS1, inhibited cell-free and cell-associated HIV-1 with particularly low IC50, in the nM to pM range, including some viral strains that were resistant to the parent molecule mCD4.1. These chemically defined molecules, which target major sites of vulnerability of gp120, are stable for at least 48?hours in conditions replicating the vaginal milieu (37?°C, pH 4.5). They efficiently mimic several large gp120 ligands, including CD4, coreceptor or neutralizing antibodies, to which their efficacy compares very favorably, despite a molecular mass reduced to 5500?Da. Together, these results support the development of such molecules as potential microbicides.

SUBMITTER: Arien KK

PROVIDER: S-EPMC5056392 | biostudies-other | 2016 Oct

REPOSITORIES: biostudies-other

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CD4-mimetic sulfopeptide conjugates display sub-nanomolar anti-HIV-1 activity and protect macaques against a SHIV162P3 vaginal challenge.

Ariën Kevin K KK Baleux Françoise F Desjardins Delphine D Porrot Françoise F Coïc Yves-Marie YM Michiels Johan J Bouchemal Kawthar K Bonnaffé David D Bruel Timothée T Schwartz Olivier O Le Grand Roger R Vanham Guido G Dereuddre-Bosquet Nathalie N Lortat-Jacob Hugues H

Scientific reports 20161010

The CD4 and the cryptic coreceptor binding sites of the HIV-1 envelope glycoprotein are key to viral attachment and entry. We developed new molecules comprising a CD4 mimetic peptide linked to anionic compounds (mCD4.1-HS<sub>12</sub> and mCD4.1-PS1), that block the CD4-gp120 interaction and simultaneously induce the exposure of the cryptic coreceptor binding site, rendering it accessible to HS<sub>12</sub>- or PS1- mediated inhibition. Using a cynomolgus macaque model of vaginal challenge with ...[more]

PMID: 27721488

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Project description:BackgroundThe menstrual cycle influences HIV infection-risk in women, although the timing and underlying mechanism are unclear. Here we investigated the contribution of the menstrual cycle to HIV susceptibility through evaluating immune behavior with infection-risk over time.MethodsBlood and vaginal lavage samples were collected from 18 pig-tailed macaques to evaluate immune changes over reproductive cycles, and from 5 additional animals undergoing repeated vaginal exposures to simian HIV (SHIV). Peripheral blood mononuclear cell (PBMC) samples from healthy women (n = 10) were prospectively collected over the course of a menstrual cycle to profile T cell populations. Immune properties from PBMC and vaginal lavage samples were measured by flow cytometry. Plasma progesterone was measured by enzyme immunoassay. The oscillation frequency of progesterone concentration and CCR5 expression on CD4 T cells was calculated using the Lomb-Scargle periodogram. SHIV infection was monitored in plasma by RT-PCR. Immune measures were compared using generalized estimating equations (GEE).FindingsMacaques cycle-phases were associated with fluctuations in systemic immune properties and a type-1 inflammatory T cell response with corresponding CCR5+ memory CD4 T cell (HIV target cell) infiltration into the vaginal lumen at the late luteal phase. Power spectral analysis identified CCR5 oscillation frequencies synchronized with reproductive cycles. In a repetitive low-dose vaginal challenge model, productive SHIV163P3 infection only occurred during intervals of mounting type-1 T cell responses (n = 5/5). Finally, we identify similar type-1 inflammatory T cell responses over the menstrual cycle are occurring in healthy women.InterpretationThese data demonstrate that periodic shifts in the immune landscape under menstrual cycle regulation drives bystander CCR5+ CD4 T cell recruitment and HIV susceptibility in the female reproductive tract.FundingThis study was supported by the U.S. Centers for Disease Control and Prevention, Atlanta, GA 30329 and NIH grants to Emory University (K23AI114407 to A.N.S., the Emory University Center for AIDS research [P30AI050409], and Atlanta Clinical and Translational Sciences Institute [KLR2TR000455, UL1TR000454]).DisclaimerThe findings and conclusions in this report are those of the authors and do not necessarily represent the views of the U.S. Centers for Disease Control and Prevention or the Department of Health and Human Services.

Dataset Information

CD4-mimetic sulfopeptide conjugates display sub-nanomolar anti-HIV-1 activity and protect macaques against a SHIV162P3 vaginal challenge.

Publications

CD4-mimetic sulfopeptide conjugates display sub-nanomolar anti-HIV-1 activity and protect macaques against a SHIV162P3 vaginal challenge.

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