Characterization of an ART-free, antibody mediated establishment of an SIV reservoir

About This Grant

PROJECT SUMMARY Antiretroviral drug therapy (ART) is the gold standard for HIV therapy for suppressing HIV infection. However, these small molecule drugs cannot eliminate the viral reservoir and thus, ART is a life-long therapy. Broadly neutralizing antibodies (bNAbs) could supplement ART and be used to reduce the viral reservoir through their Fc effector functions. While passive infusion of multiple active bNAbs can suppress viremia after ART is lifted, this strategy still requires the need for multiple infusions to maintain therapeutic concentrations of the bNAbs. We have been using adeno-associated virus (AAV) vectors to deliver HIV bNAbs, SIV bNAbs, and antibody-like inhibitors. AAV vectors provide means for long-term expression of bNAbs at concentrations capable of maintaining viral suppression via a one-time intramuscular administration. One issue that has been plaguing the field, especially in nonhuman primate models, is the development of host anti-drug antibodies and immune responses against the expressed bNAbs. We have recently demonstrated that targeting the immune checkpoint pathway is a promising target to limit the host immune response after vector administration. This work has resulted in consistent expression of two HIV bNAbs in rhesus macaques at concentrations thought to be in therapeutic range to suppress an HIV or SIV infection. Additionally, our work in developing eCD4-Ig, an antibody-like HIV entry inhibitor, has produced promising prophylaxis results in rhesus macaques against SHIV and SIV challenges. Because eCD4-Ig neutralizes all HIV-1, HIV-2, and SIV isolates and no escape mutations have been identified to date, it is a powerful inhibitor to combine with bNAbs for HIV and SIV therapy. Unlike ART, both antibodies and eCD4-Ig can kill infected cells, thus, providing a promising strategy to reduce and eliminate the viral reservoir. Therefore, we hypothesize combining AAV-delivered eCD4-Ig with antibodies would generate a unique viral reservoir upon suppression in the absence of ART, both characteristically and quantitatively. In Aim 1, we will optimize our AAV delivery strategy for multiple SIV antibodies and eCD4-Ig. In Aim 2, we will characterize and quantify the viral reservoir upon suppression when mediated by SIV bNAbs and eCD4-Ig compared to ART. In Aim 3, we will determine whether AAV-delivered SIV bNAbs and eCD4-Ig can increase the rate of viral reservoir decay compared to ART. These results would provide a foundation for AAV-delivered inhibitors as an alternative to ART and move the field closer to realizing an HIV cure.