While the overwhelming scope of tragic outcomes from HIV infection at the origin of the AIDS epidemic are in the past, those living with HIV still require daily treatments. One option includes combination antiretroviral therapy (cART) which can suppress viral replication to undetectable levels. While this therapy is effective, HIV-infected CD4+ T cells still remain in the body and inconsistent adherence to therapy schedules can result in increased viral replication to detectable levels, possibly also causing symptoms.
Treatment with C-C chemokine receptor 5 (CCR5)-specific antibodies are one of a few alternative therapies for HIV infection, however dosing strategies and maintenance is challenging for both patients and manufacturers.
Researchers at Oregon Health & Science University Oregon National Primate Research Center aimed to address the need for long-term expression of CCR5-specific antibodies to establish protection from HIV using adeno-associated virus (AAV) vectors.
Their work was published in Science Translational Medicine under the title, “Adeno-associated virus gene therapy-mediated CCR5 blockade suppresses virus replication long-term in SHIV-infected macaques.”
“We explored the ability of AAV vectors expressing the CCR5-blocking antibody leronlimab to mediate a functional cure in simian-human immunodeficiency virus (SHIV)–infected rhesus macaques by interrupting viral access to the viral entry co-receptor CCR5,” wrote the authors.
Leronlimab is an antiviral HIV drug that targets and blocks the CCR5 receptor, thus blocking HIV’s ability to invade immune cells. Nineteen SHIV-infected macaques were treated with leronlimab expressing AAVs. All but one treated macaque produced detectable levels of leronlimab following AAV administration. The single animal that didn’t produce leronlimab had preexisting leronlimab-specific antidrug antibodies (ADA).
About half of the animals developed an immune response to the therapy, producing ADA clearing of leronlimab, however, over a year of observation, researchers found latent increase in stable expression of the leronlimab. Macaques that did not exhibit an immune response maintained leronlimab expression throughout the same year of observation.
Most macaques that produced sufficient number of antibodies showed long-term partial or full suppression of SHIV. “Of the nine macaques producing sufficient leronlimab to achieve full CCR5 receptor occupancy on blood CD4+ T cells, AAV-leronlimab drove stringent or partial control of SHIV viremia in six macaques long term,” wrote the authors. The three remaining macaques, when given an additional dose of leronlimab, showed either complete viral suppression or 100-fold reduction in viral load.
The authors explain that these results indicate that there is a “threshold of leronlimab expression [that] is necessary to effectively halt SHIV replication.” They also point out that while they tested multiple capsids and promotors, they were limited in assessing vector design or dose, but surmise that the AAV-leronlimab could be combined with other AAV-delivered antivirals for a multitargeted approach.
“These results demonstrate the potential of gene therapy–mediated long-term antibody-based CCR5 blockade for HIV functional cure but highlight challenges in achieving sufficient antibody expression when targeting an abundant self-antigen,” concluded the authors.
