Promise and Progress of an HIV-1 Cure by Adeno-Associated Virus Vector Delivery of Anti-HIV-1 Biologics

Abstract

Despite the success of antiretroviral therapy (ART) at suppressing HIV-1 infection, a cure that eradicates all HIV-1-infected cells has been elusive. The latent viral reservoir remains intact in tissue compartments that are not readily targeted by the host immune response that could accelerate the rate of reservoir decline during ART. However, over the past decade, numerous broadly neutralizing antibodies (bNAbs) have been discovered and characterized. These bNAbs have also given rise to engineered antibody-like inhibitors that are just as or more potent than bNAbs themselves. The question remains whether bNAbs and HIV-1 inhibitors will be the effective "kill" to a shock-and-kill approach to eliminate the viral reservoir. Additional research over the past few years has sought to develop recombinant adeno-associated virus (rAAV) vectors to circumvent the need for continual administration of bNAbs and maintain persistent expression in a host. This review discusses the advancements made in using rAAV vectors for the delivery of HIV-1 bNAbs and inhibitors and the future of this technology in HIV-1 cure research. Numerous groups have demonstrated with great efficacy that rAAV vectors can successfully express protective concentrations of bNAbs and HIV-1 inhibitors. Yet, therapeutic concentrations, especially in non-human primate (NHP) models, are not routinely achieved. As new studies have been reported, more challenges have been identified for utilizing rAAV vectors, specifically how the host immune response limits the attainable concentrations of bNAbs and inhibitors. The next few years should provide improvements to rAAV vector delivery that will ultimately show whether they can be used for expressing bNAbs and HIV-1 inhibitors to eliminate the HIV-1 viral reservoir.

Riboswitches for Controlled Expression of Therapeutic Transgenes Delivered by Adeno-Associated Viral Vectors

“…However, transient immunosuppression during AAV administration has been shown to reduce the occurrence of anti-transgene immunity and improve expression levels [217,236]. RNA off-switches could serve as a safer alternative to immunosuppression, allowing coadministration of AAV and an off-switch ligand which suppresses transgene expression until the heightened immune surveillance observed to follow vector administration has subsided [237]. In addition, the US Defense Advanced Research Projects Agency (DARPA) has developed the PREPARE program, which seeks to achieve inducible, transient expression of protective transgene products in military service members, first responders, and civilians [238].…”

HIV-1 Entry and Prospects for Protecting against Infection

“…Increasing efforts in antibody engineering to improve half-life and safety make passive immunization strategies exceedingly attractive. An example of advanced immunoprophylaxis is adeno-associated virus-mediated antibody gene delivery [ 292 , 293 ], which could be an alternative to vaccination to induce sustained expression of HIV nAbs.…”

Broadly Neutralizing Antibodies for HIV-1 Prevention

“…Multiple bnAbs currently in clinical development are being tested with the LS mutations, and it is hoped that such improvements in the pharmacokinetic profiles of bnAbs may make it possible to achieve and maintain therapeutic levels with lower-dose and less frequent administrations. Strategies for persistent expression of bnAbs in vivo by vectored antibody gene delivery using rAAV have shown promise in humanized mouse and NHP models of infection ( 122 ), and one clinical trial has evaluated rAAV1 delivery of the V2-glycan targeting bnAb PG9 in humans (NCT01937455) ( 81 ). While this study demonstrated that rAAV delivery was safe and well tolerated, there was no detection of PG9 in serum by ELISA, and the development of ADA and anti-vector antibody responses was observed in several volunteers, thus highlighting the challenges that remain for developing such approaches.…”