We have recently published our research that characterizes eCD4-Ig. eCD4-Ig is an antibody-like HIV entry inhibitor that fuses a sulfated CCR5-mimetic peptide to the C-terminus of CD4-Ig. Based on neutralization assay data, eCD4-Ig is broader than and equally potent as some of the best described HIV-1 broadly neutralizing antibodies to date. eCD4-Ig neutralized all isolates tested including 38 HIV-1 isolates resistant to 3BNC117 or NIH45-46, HIV-2, SIVmac239, SIVmac251, and isolates that use CXCR4 as their coreceptor. The addition of the CCR5-mimetic peptide allowed eCD4-Ig to have higher affinity for cell surface-expressed HIV-1 Env and also limited viral enhancement caused by sub-neutralizing levels of CD4-Ig. Using adeno-associated virus (AAV) vectors, we have shown that a rhesus form of eCD4-Ig can be expressed in four rhesus macaques for over one year with no harm to the animals. The rh- eCD4-Ig protein titers were at levels that protected all four macaques from multiple SHIV-AD8 challenges up to 16-times the AID50 (Animal Infectious Dose 50). We did observe a measurable anti- transgene response to the expressed rh-eCD4-Ig protein, but the response was not near the levels seen against AAV-delivered HIV-1 antibodies. Yet, even a relatively modest immune response to the delivered transgene can limit the inhibitor?s efficacy in vivo. With these encouraging data, this proposal seeks to answer two main questions: (1) Can AAV-expressed eCD4-Ig be used as a therapy to maintain viral suppression in SHIV infected macaques? (2) Can interferon-induced miRNAs regulate transgene expression from AAV vectors to limit the host immune response to the transgene? With the primary goal of using eCD4-Ig as an alternative to antiretroviral therapies, answering these two questions will continue to build on the safety and efficacy of AAV-delivered eCD4-Ig as well as realizing the complete potential of AAV vectors used for gene therapy.

Public Health Relevance

We have recently published our work characterizing eCD4-Ig, a broad and potent HIV entry inhibitor that is safe and functional when used in a gene therapy vector. Here we will assess whether AAV- delivered eCD4-Ig is a viable HIV-1 therapy by determining whether AAV-delivered eCD4-Ig can maintain viral suppression in SHIV infected macaques. We will also explore the use of interferon- induced miRNAs as a means of limiting the host immune response against AAV-delivered transgenes in an effort to improve AAV vectors for gene therapy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F17-M (20)L)
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Conley, Tony J
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Scripps Florida
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Fetzer, Ina; Gardner, Matthew R; Davis-Gardner, Meredith E et al. (2018) eCD4-Ig Variants That More Potently Neutralize HIV-1. J Virol 92:
Davis-Gardner, Meredith E; Gardner, Matthew R; Alfant, Barnett et al. (2017) eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients. PLoS Pathog 13:e1006786
Gardner, Matthew R; Farzan, Michael (2017) Engineering antibody-like inhibitors to prevent and treat HIV-1 infection. Curr Opin HIV AIDS :