Research Article: A Subset of Latency-Reversing Agents Expose HIV-Infected Resting CD4+ T-Cells to Recognition by Cytotoxic T-Lymphocytes

Date Published: April 15, 2016

Publisher: Public Library of Science

Author(s): R. Brad Jones, Stefanie Mueller, Rachel O’Connor, Katherine Rimpel, Derek D. Sloan, Dan Karel, Hing C. Wong, Emily K. Jeng, Allison S. Thomas, James B. Whitney, So-Yon Lim, Colin Kovacs, Erika Benko, Sara Karandish, Szu-Han Huang, Maria J. Buzon, Mathias Lichterfeld, Alivelu Irrinki, Jeffrey P. Murry, Angela Tsai, Helen Yu, Romas Geleziunas, Alicja Trocha, Mario A. Ostrowski, Darrell J. Irvine, Bruce D. Walker, David T. Evans.

http://doi.org/10.1371/journal.ppat.1005545

Abstract

Resting CD4+ T-cells harboring inducible HIV proviruses are a critical reservoir in antiretroviral therapy (ART)-treated subjects. These cells express little to no viral protein, and thus neither die by viral cytopathic effects, nor are efficiently cleared by immune effectors. Elimination of this reservoir is theoretically possible by combining latency-reversing agents (LRAs) with immune effectors, such as CD8+ T-cells. However, the relative efficacy of different LRAs in sensitizing latently-infected cells for recognition by HIV-specific CD8+ T-cells has not been determined. To address this, we developed an assay that utilizes HIV-specific CD8+ T-cell clones as biosensors for HIV antigen expression. By testing multiple CD8+ T-cell clones against a primary cell model of HIV latency, we identified several single agents that primed latently-infected cells for CD8+ T-cell recognition, including IL-2, IL-15, two IL-15 superagonists (IL-15SA and ALT-803), prostratin, and the TLR-2 ligand Pam3CSK4. In contrast, we did not observe CD8+ T-cell recognition of target cells following treatment with histone deacetylase inhibitors or with hexamethylene bisacetamide (HMBA). In further experiments we demonstrate that a clinically achievable concentration of the IL-15 superagonist ‘ALT-803’, an agent presently in clinical trials for solid and hematological tumors, primes the natural ex vivo reservoir for CD8+ T-cell recognition. Thus, our results establish a novel experimental approach for comparative evaluation of LRAs, and highlight ALT-803 as an LRA with the potential to synergize with CD8+ T-cells in HIV eradication strategies.

Partial Text

Current antiretroviral (ARV) treatment regimens effectively suppress HIV replication, but are unable to cure infection. Viral persistence in long term cellular reservoirs leaves even well-treated individuals with a lifelong commitment to drug regimens, burdened by co-morbidities such as cardiovascular disease and neurocognitive disorders, and exposed to the negative social issues that come with being HIV-positive[1–3]. The development of therapeutic strategies capable of eradicating virus from individuals would greatly improve the lives of people living with HIV/AIDS.

Our study is based on the premise that, in facing the challenge of eradicating HIV infection, effectively harnessing the host immune response is likely to be paramount. From this vantage, immune effectors should be integrated into early stages of evaluating potential latency reversal strategies, with the optimal LRA being one that achieves a sufficient threshold of reactivation (submaximal) to expose infected cells to the immune system, and enhances the abilities of immune effectors to eliminate these cells. In a primary cell model, we identified four compounds that exposed latently-infected cells for recognition by HIV-specific CD8+ T-cells. In contrast, we were not able to observe recognition of latently-infected cells following treatment with HMBA or with HDAC inhibitors. As with all negative results, the latter observation comes with caveats, such as assay sensitivity. We also acknowledge the limitations of performing these experiments in a primary CD4+ T-cell model of latency, rather than against the natural reservoir. These results should, however, contribute to the ongoing discussion regarding the degree of latency reversal that is achieved by HDAC inhibitors. Based on our data, inefficient induction of antigen presentation by HDAC inhibitors should be considered as a potential contributing factor underlying the observation that, thus far, clinical trials of these drugs have not achieved reductions in viral reservoirs.

 

Source:

http://doi.org/10.1371/journal.ppat.1005545

 

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