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.

Keywords: HIV-1; HIV-1 cure; adeno-associate virus; broadly neutralizing antibodies (bNAbs); eCD4-Ig.

Figure 1

Process for selecting a bNAb/inhibitor cocktail for delivery by rAAV vectors. Similar to ART, it is highly unlikely that a single bNAb or inhibitor cocktail will be effective for every individual living with HIV-1. Therefore, cocktails will most likely be tailored to the viral swarm present for each individual or endemic region. Initial screening will need to be conducted on the preexisting viral swarm to identify which bNAbs or inhibitors have activity against that swarm. rAAV vectors that encode each of the individual components of the cocktail will need to be produced. Delivery of the rAAV vectors will then yield a cocktail of inhibitors made by individual that target the HIV-1 swarm and suppress infection.

Figure 2

Possible outcomes from rAAV-mediated bNAb therapy. (A) In the scenario where rAAV-delivered bNAbs (blue arrow) are used to treat chronic infection, if the bNAb concentrations do not reach therapeutic levels, no viral suppression will be observed and viral escape from the bNAbs will be likely (left). However, therapeutic concentrations may suppress viremia and provide a functional cure for the individual (right). (B) In individuals treated with ART, low concentrations of rAAV-expressed bNAbs will likely result in viral rebound (left). High concentrations of bNAbs will maintain viral suppression after ART lift and provide a functional cure (right). (C) Should therapeutic concentrations maintain viral suppression after ART lift, LRAs (purple arrows) may be administered to stimulate replication (viral load blips) in latently infected cells and provide a target for bNAbs. If this approach is successful, a measurable decrease in the viral reservoir should be observed and eventually lead the individual to being cured of the HIV-1 infection.