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.
Highlights
The 2019 UNAIDS Report and World Health Organization both estimate that there are ∼38 million people living with HIV-1 infection (UNAIDS, 2019; WHO, 2019)
As noted in this review, broadly neutralizing antibodies (bNAbs) and HIV-1 inhibitors may play a role as part of an HIV-1 cure, but questions persist whether these drugs can impact the rate of decay of the reservoir
The Miami Monkey provides the field with evidence that recombinant adeno-associated virus (rAAV) vectors could be part of a “one-shot cure” in that these vectors could provide long-term expression of bNAbs and inhibitors and at therapeutic concentrations, suppress an HIV-1 infection in place of daily antiretroviral therapy (ART)
Summary
The 2019 UNAIDS Report and World Health Organization both estimate that there are ∼38 million people living with HIV-1 infection (UNAIDS, 2019; WHO, 2019). ITS01 was observed to express at higher concentrations than ITS06.02, and in only 20% of the animals that received rAAV8 vectors did macaques generate ADA responses against the expressed antibody. In addition to studying rAAV delivered HIV-1 bNAbs, our lab has evaluated the protective efficacy of rAAV1 expressed eCD4-Ig in rhesus macaques (Gardner et al, 2015, 2019a).
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