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.
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.
| 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 : |
