Non-viral gene therapy with eCD4-Ig

ABSTRACT We are developing non-viral gene therapy with eCD4-Ig as a practical approach for suppressing HIV replication for a lifetime after a one-time intramuscular injection. The error-prone nature of reverse transcriptase, and the sequence plasticity of the HIV envelope glycoprotein (Env), result in the rapid escape of neutralizing antibodies and daunting levels of global antigenic diversity. The antigenic diversity of HIV and ease of escape of antibody responses can be countered with eCD4-Ig, which is an antibody-like therapeutic protein constructed from parts of HIV’s primary receptor (CD4) and coreceptor (CCR5). eCD4-Ig functions like a broadly-neutralizing antibody (bNAb) in being able to neutralize virus infection and mediate effector functions, but cannot be escaped without HIV sacrificing its ability to bind its receptor and coreceptor. Here, we propose developing a non-viral gene therapy platform and its use to sustain therapeutically-effective plasma concentrations of eCD4-Ig for potentially a lifetime after a single administration. We propose basic science experiments that will inform the development of this non-viral gene therapy platform, plus the development of approaches for enhancing the efficiency of gene transfer into skeletal muscle. The proposed studies build on our work with adeno-associated virus (AAV) vectors to establish a state of long-term viral remission where further treatment is not required to suppress plasma viral loads to levels that are undetectable using standard assays. We and others term such a state of long-term viral suppression, albeit one short of eradication, a ‘functional cure.’ The lifelong expression of therapeutic concentrations of eCD4- Ig after a one-time intramuscular administration of a non-viral gene therapy vector is a feasible means of achieving a functional cure for HIV.