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Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells
Szu-Han Huang, … , Bruce D. Walker, R. Brad Jones
Szu-Han Huang, … , Bruce D. Walker, R. Brad Jones
Published January 22, 2018
Citation Information: J Clin Invest. 2018;128(2):876-889. https://doi.org/10.1172/JCI97555.
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Research Article AIDS/HIV Immunology

Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells

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Abstract

The presence of persistent, latent HIV reservoirs in CD4+ T cells obstructs current efforts to cure infection. The so-called kick-and-kill paradigm proposes to purge these reservoirs by combining latency-reversing agents with immune effectors such as cytotoxic T lymphocytes. Support for this approach is largely based on success in latency models, which do not fully reflect the makeup of latent reservoirs in individuals on long-term antiretroviral therapy (ART). Recent studies have shown that CD8+ T cells have the potential to recognize defective proviruses, which comprise the vast majority of all infected cells, and that the proviral landscape can be shaped over time due to in vivo clonal expansion of infected CD4+ T cells. Here, we have shown that treating CD4+ T cells from ART-treated individuals with combinations of potent latency-reversing agents and autologous CD8+ T cells consistently reduced cell-associated HIV DNA, but failed to deplete replication-competent virus. These CD8+ T cells recognized and potently eliminated CD4+ T cells that were newly infected with autologous reservoir virus, ruling out a role for both immune escape and CD8+ T cell dysfunction. Thus, our results suggest that cells harboring replication-competent HIV possess an inherent resistance to CD8+ T cells that may need to be addressed to cure infection.

Authors

Szu-Han Huang, Yanqin Ren, Allison S. Thomas, Dora Chan, Stefanie Mueller, Adam R. Ward, Shabnum Patel, Catherine M. Bollard, Conrad Russell Cruz, Sara Karandish, Ronald Truong, Amanda B. Macedo, Alberto Bosque, Colin Kovacs, Erika Benko, Alicja Piechocka-Trocha, Hing Wong, Emily Jeng, Douglas F. Nixon, Ya-Chi Ho, Robert F. Siliciano, Bruce D. Walker, R. Brad Jones

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Figure 2

Ex vivo CD8+ T cells in combination with IL-15SA, Pam3CSK4, or bryostatin, drive reductions in HIV DNA but not intact-inducible HIV reservoirs.

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Ex vivo CD8+ T cells in combination with IL-15SA, Pam3CSK4, or bryostati...
(A) CD8+ T cells from participant OM5334, treated during acute/early infection, were cultured in a HIVE assay with IL-15SA or Pam3CSK4, as indicated. ddPCR results show the mean ± SD, with P values calculated by 1-way ANOVA with Tukey’s multiple comparison tests. (B) CD4+ T cells isolated from HIVE assay were injected into 3 NSG mice per condition. Shown are the mean ± SEM viral loads, indicating no significant differences in time to viral rebound. (C) ddPCR results for participant OM5011, treated during chronic infection. Treatment with CD8+ T cells + IL-15SA in this HIVE assay resulted in significant decreases in HIV DNA (P = 0.05). (D) QVOA results from the HIVE assay in C, showing estimated IUPM ± 95% CIs. (E) CD8+ T cells from participant CIRC0311, treated during chronic infection, were expanded following HIV peptide stimulation, then used in HIVE assays with IL-15SA or bryostatin; treatment with LRA + CD8+ T cells led to significant decreases in HIV DNA for both IL-15SA and bryostatin (P < 0.05). (F) QVOA from CD4+ T cells purified from the CIRC0311 HIVE assay shows no decrease in IUPM between LRA-only and LRA + CD8+ T cells conditions. NS, not significant.
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