HIV remains an incurable viral infection and a significant global health concern. Despite the advent of antiretroviral therapy, there are 36.9 million recorded cases of HIV worldwide, with an additional 1.8 million new infections recorded in 2017 alone. An HIV cure is therefore one of several priorities within the field, and will require HIV “reservoir” cells—comprised of latently-HIV infected CD4+ T cells and productively-infected, tissue resident macrophages—to be selectively killed in vivo.
HIV reservoir cells are rarely found within the peripheral circulation, residing instead within inaccessible tissue sanctuaries. Consequently, their characterization has been limited to in vitro laboratory models. To complicate matters further, a definitive cellular surface marker of HIV infected cells has yet to be identified. Impairment of the type I interferon (IFN1) response has been observed during HIV infection, however, making it a unique intracellular maker of HIV-infected cells. The recent development of oncolytic viruses (OV) designed to selectively kill IFN-defective cancer cells also suggests that these IFN1 defects possess therapeutic value.
It was therefore hypothesized that the impairment of the IFN1 response in HIV-infected CD4+ cells and macrophages could serve as a target for oncolytic virus-mediated killing. The induction of several antiviral IFN-stimulated proteins, including PKR and ISG15, was inhibited in HIV-infected monocyte-derived macrophages (MDM) following stimulation with IFNα or a synthetic RNA. Consequently, HIV-infected MDM were more susceptible to infection and killing by the oncolytic Maraba virus, MG1. Importantly, MG1-mediated killing required the presence of replication-competent OV, and could not be potentiated by UV-inactivated MG1 or supernatants from MG1-infected cells. The ability of MG1 to target the HIV reservoir was further confirmed using alveolar macrophages collected from the lungs of cART-suppressed individuals living with HIV.
These findings indicate that IFN1 defects are a feature of HIV infected cells, which can be exploited for selective killing by OV. This project is therefore unique in that it demonstrates that HIV reservoir cells can be eradicated in a targeted manner by exploiting an intracellular marker of HIV infection. As MG1-based cancer therapies are currently being explored in Phase I/II clinical trials, there is potential for this approach to be adapted for use within the HIV cure field.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/39249 |
| Date | 28 May 2019 |
| Creators | Sandstrom, Teslin Stella |
| Contributors | Angel, Jonathan B. |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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