Toward a Nano-Immunological Strategy to Eliminate HIV-1 Reservoirs
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HIV remains a global pandemic, with an estimated 40 million people living with HIV (PLWH) as of 2023. Antiretroviral therapy (ART) effectively suppresses human immunodeficiency virus type 1 (HIV-1) replication, but is not a cure for HIV/AIDS. The virus persists within latent reservoirs, and upon interruption or cessation of ART, viral rebound occurs rapidly, requiring patients to adhere to a lifelong ART regimen. Chronic inflammation due to underlying infection and continual exposure to ART are associated with co-morbidities such as cardiovascular disease and neurocognitive disorders, thus a novel therapy capable of eradicating the virus remains an unmet need. Natural killer (NK) cells are attractive immune cells for treating HIV, as they are efficient at killing infected CD4 T cells, secreting anti-viral cytokines including TNF-α and IFNγ to limit infection, and are themselves insusceptible to CD4-mediated infection. HIV also downregulates HLA class I expression on infected cells to escape recognition by effector T cells, but triggers NK cytotoxicity. In particular, NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) is linked with slower progression of HIV infection, increased capacity of NK cells to lyse allogeneic HIV-infected T cells, and enhanced viral control in elite controllers. However, NK cell-mediated ADCC of HIV-infected cells requires the local availability of an HIV-specific antibody in the physical context of NK cells and exposed HIV antigen, which is often absent in latently infected cells. Broadly neutralizing antibodies (bnAbs) recognize envelope epitopes on HIV and have shown promise in neutralizing the virus and maintaining virologic control in the absence of ART. However, latently infected cells do not produce ample virus, so bnAb binding sites are inaccessible in latent reservoirs. We have developed a coordinated approach that combines the release of the pro-inflammatory cytokine TNF-α – serving as a model latency reversing agent (LRA) – and the bnAb 3BNC117 using biodegradable polymeric nanodepots (NDs) made from poly(lactic-co-glycolic acid) (PLGA). The TNF-α-3BNC117-NDs were synthesized using the nanoprecipitation technique. The co-localization of an LRA and an HIV-specific bnAb using a nanoparticle delivery vehicle triggered enhanced elimination of latently infected T cells when administered in conjunction with NK cells. This dissertation presents the physicochemical characterization of TNF-α-3BNC117-NDs, assesses their biodistribution to reservoir niches in murine models, and demonstrates their capacity to simultaneously reactivate latent HIV, opsonize infected cells with bnAb, and facilitate the elimination of infected cells.
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