RESEARCH ARTICLE


Protection Efficacy of C5A Against Vaginal and Rectal HIV Challenges in Humanized Mice



Philippe A. Gallay1, *, Udayan Chatterji1, Aaron Kirchhoff1, Angel Gandarilla1, Richard B. Pyles2, Marc M. Baum3, John A. Moss3
1 Department of Immunology & Microbiology, The Scripps Research Institute; La Jolla, California 92037, USA
2 Department of Pediatrics, University of Texas Medical Branch; Galveston, Texas 77555-0436, USA
3Department of Chemistry, Oak Crest Institute of Science; Monrovia, California 91107. USA


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© 2018 Gallay et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Department of Immunology & Microbiology, The Scripps Research Institute, Philippe A. Gallay , IMM-9, 10550 N. Torrey Pines Rd, La Jolla, USA; Tel: (858) 784-8180; E-mail: gallay@scripps.edu


Abstract

Introduction:

In the absence of a vaccine, there is an urgent need for the identification of effective agents that prevent HIV transmission in uninfected individuals. Non-vaccine Biomedical Prevention (nBP) methods, such as topical or systemic pre-exposure prophylaxis (PrEP), are promising strategies to slow down the spread of AIDS.

Methods:

In this study, we investigated the microbicidal efficacy of the viral membrane-disrupting amphipathic SWLRDIWDWICEVLSDFK peptide called C5A. We chose the bone marrow/liver/thymus (BLT) humanized mouse model as vaginal and rectal HIV transmission models.

Results:

We found that the topical administration of C5A offers complete protection against vaginal and rectal HIV challenges in humanized mice. After demonstrating that C5A blocks genital HIV transmission in humanized mice, we examined the molecular requirements for its microbicidal property. We found that the removal of four amino acids on either end of C5A does not diminish its microbicidal efficacy. However, the removal of four amino acids at both the ends, abolishes its capacity to prevent vaginal or rectal HIV transmission, suggesting that the length of the peptide is a critical parameter for the microbicidal activity of C5A. Moreover, we demonstrated that the amphipathicity of the helical peptide as well as its hydrophobic surface represents key factors for the microbicidal activity of C5A in humanized mice.

Conclusion:

With its noncellular cytotoxic activity, its property of neutralizing both HSV and HIV, and its unique mechanism of action that disrupts the stability of the viral membrane, C5A represents an attractive multipurpose microbicidal candidate to be combined with other anti-HIV agents including antiretrovirals.

Keywords: HIV transmission, Microbicide, Bone marrow/Liver/Thymus Mice, C5A, Vaginal challenge, Rectal challenge.