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

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 HoRobert F Siliciano, Bruce D. Walker, R. Brad Jones

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)876-889
Number of pages14
JournalJournal of Clinical Investigation
Volume128
Issue number2
DOIs
StatePublished - Feb 1 2018

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HIV
T-Lymphocytes
Proviruses
Cytotoxic T-Lymphocytes
Virus Replication
Cell- and Tissue-Based Therapy
Infection
Viruses
DNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Huang, S. H., Ren, Y., Thomas, A. S., Chan, D., Mueller, S., Ward, A. R., ... Brad Jones, R. (2018). Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ t cells. Journal of Clinical Investigation, 128(2), 876-889. https://doi.org/10.1172/JCI97555

Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ t cells. / Huang, Szu Han; Ren, Yanqin; Thomas, Allison S.; Chan, Dora; Mueller, Stefanie; Ward, Adam R.; Patel, Shabnum; Bollard, Catherine M.; Cruz, Conrad Russell; Karandish, Sara; Truong, Ronald; Macedo, Amanda B.; Bosque, Alberto; Kovacs, Colin; Benko, Erika; Piechocka-Trocha, Alicja; Wong, Hing; Jeng, Emily; Nixon, Douglas F.; Ho, Ya Chi; Siliciano, Robert F; Walker, Bruce D.; Brad Jones, R.

In: Journal of Clinical Investigation, Vol. 128, No. 2, 01.02.2018, p. 876-889.

Research output: Contribution to journalArticle

Huang, SH, Ren, Y, Thomas, AS, Chan, D, Mueller, S, Ward, AR, Patel, S, Bollard, CM, Cruz, CR, Karandish, S, Truong, R, Macedo, AB, Bosque, A, Kovacs, C, Benko, E, Piechocka-Trocha, A, Wong, H, Jeng, E, Nixon, DF, Ho, YC, Siliciano, RF, Walker, BD & Brad Jones, R 2018, 'Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ t cells', Journal of Clinical Investigation, vol. 128, no. 2, pp. 876-889. https://doi.org/10.1172/JCI97555
Huang, Szu Han ; Ren, Yanqin ; Thomas, Allison S. ; Chan, Dora ; Mueller, Stefanie ; Ward, Adam R. ; Patel, Shabnum ; Bollard, Catherine M. ; Cruz, Conrad Russell ; Karandish, Sara ; Truong, Ronald ; Macedo, Amanda B. ; Bosque, Alberto ; Kovacs, Colin ; Benko, Erika ; Piechocka-Trocha, Alicja ; Wong, Hing ; Jeng, Emily ; Nixon, Douglas F. ; Ho, Ya Chi ; Siliciano, Robert F ; Walker, Bruce D. ; Brad Jones, R. / Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ t cells. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 2. pp. 876-889.
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