Monday, January 20, 2025
1/20/2025
PROJECT SUMMARY Adeno-associated virus (AAV)-mediated gene therapy with broadly (b) neutralizing (n) antibodies (Abs) holds great promise for preventing and treating HIV infection. This approach is unique in that host cells, after receiving the relevant genes through AAV transduction, can immediately begin to secrete bnAbs into the circulation. Because AAV is non-pathogenic and its genome persists in host cells, successful AAV transduction of long-lived cells, such as muscle cells, can result in continuous expression of bnAbs for years, possibly decades. Since realizing this vision in humans would dramatically simplify efforts to combat the HIV/AIDS pandemic, this project focuses on overcoming a key obstacle to the clinical use of AAV/bnAb therapy: the high prevalence of anti-AAV nAbs in humans. Anti-AAV nAbs target the AAV capsid and are mainly induced by natural infection with wild-type (WT) AAV, which is endemic in primates. AAV seroprevalence varies geographically, ranging from 30% to 100%, depending on the AAV serotype. Because of structural similarities among different capsids, nAbs induced by infection with WT AAV often cross-react with other AAV serotypes, including those used for gene therapy. This is problematic because, depending on the nAb titer, Ab-mediated neutralization of AAV vectors can reduce or even abrogate transduction. Hence, AAV seropositive (+) individuals are currently excluded from clinical trials of AAV-based gene therapies. These observations, viewed in the context of the 38 million people living with HIV (PLWH) worldwide who could benefit from AAV/bnAb therapy, highlight the need to develop strategies to overcome pre-existing anti-AAV nAbs. Here we propose a series of approaches to bypass humoral immunity to AAV in AAV(+) individuals, with the ultimate goal of expanding people’s access to AAV/bnAb therapy. This project has four specific aims. Our first aim is to identify the least prevalent muscle-tropic AAV capsid in sub- Saharan Africa, home of two thirds of all PLWH. Knowledge gained from this serosurvey would allow AAV(–) PLWH to benefit from AAV/bnAb therapies without any additional intervention. Aim 1 will also establish the range of pre-existing anti-AAV nAb titers that must be overcome to enable AAV transduction in field settings. Our second and third aims are to assess the extent to which transient depletion of serum IgG Abs can decrease anti-AAV nAb titers in AAV(+) rhesus macaques (RMs). Our final aim is to integrate the findings of Aims 1-3 by testing whether depleting pre-existing anti-AAV nAbs in RMs with pharmacologically controlled simian immunodeficiency virus (SIV) infection can enhance AAV-mediated delivery of eCD4-Ig–a bnAb-like molecule that potently neutralizes both HIV and SIV. Aim 4 will also assess the ability of AAV-expressed eCD4-Ig to maintain antiretroviral therapy- free control of SIV virus replication. Thus, this project will not only establish a blueprint for testing AAV-based HIV immunotherapies in the epicenter of the HIV/AIDS pandemic, but it will also expand our toolkit of interventions for evading pre-existing immunity to AAV. If successful, this research could bring us closer to achieving sustained AAV-driven production of anti-HIV biologics in people, regardless of AAV serostatus.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).