Genetically Modified Immune Cells Secreting Broadly Neutralizing Antibodies Against HIV: Restoration of Systemic Immunity
Open AccessOver 38 million people worldwide live with HIV and while antiretroviral therapy (ART) decreases viral load, increases lifespan, and reduces regression to acquired immunodeficiency syndrome (AIDS), ART is not a cure for HIV. People living with HIV remain at increased risk for opportunistic infection and for comorbidities including cancer – even in the era of ART. The need for daily adherence to ART, difficulty of distribution in poor countries, and the development of drug resistance highlights the need for continued research for an HIV cure. Studies of elite controllers, a small population (~1%) of HIV+ individuals who maintain low or undetectable levels of HIV viremia in the absence of ART, highlight several antiviral immune mechanisms with potential applications towards a functional cure. While no single antiviral mechanism correlates with HIV control, multiple antiviral immune functions are restored in this population, suggesting that education of a robust, multifaceted antiviral response is needed to control HIV. Elite controllers sustain low levels of HIV through increased HIV-specific CD8+ T cell response, CD4+ T cell function, and the ability for neutralizing antibodies to elicit ADCC.The therapeutic administration of either ex vivo expanded HIV-specific T cells (HST) or broadly neutralizing antibodies (bNAb) elicit significant, yet transient decreases in viral load. Failure of either T cell or antibody therapy alone to elicit a durable response is due to viral escape mutations, short half-life of bNAb, and innate immune dysfunction. To combat HIV-induced T cell exhaustion and epitope escape, we propose adoptive transfer of multi-epitope HIV specific T cells. To combat short half-life and innate immune dysfunction, we propose constitutive secretion of bNAb from HST and HIV+ donor derived, ex vivo expanded NK cells. Finally, to optimize antibody secretion, we propose the design of small single chain engineered antibodies with able to neutralize HIV and engage the innate immune response. Further, integrating each approach into a single therapeutic platform will facilitate a coordinated anti-HIV response across these different strategies.We thus hypothesized that the genetic medication of immune cells to secrete antibodies would elicit a multifaceted immune response against HIV through polyclonal HIV-specific T cell cytotoxicity, neutralization of cell free virus, and the ability to engage innate immune effectors to elicit antibody-dependent cellular cytotoxicity (ADCC). We demonstrated the ability to genetically modify HIV-specific T cells and NK cells to secrete broadly neutralizing antibodies. Secretion of antibody from noncanonical immune cell subsets does not impair the antibody’s effector function, nor does genetic modification impair T cell or NK cell function. Genetically modified antibody secreting T cells and NK cells demonstrated greater HIV suppression in an in vitro model compared to non-transduced donor matched cells. Finally, we demonstrated the functionality of two antibody engineering approaches, bispecific killer cell engagers and camelid derived nanobody fusion proteins, with potential future application in this platform. Overall, we showed proof-of-principle of a novel therapeutic platform for the cure of HIV, through the combination of multiple antiviral immune mechanisms by genetic modification.
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