TY - JOUR
T1 - Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ t cells
AU - Huang, Szu Han
AU - Ren, Yanqin
AU - Thomas, Allison S.
AU - Chan, Dora
AU - Mueller, Stefanie
AU - Ward, Adam R.
AU - Patel, Shabnum
AU - Bollard, Catherine M.
AU - Cruz, Conrad Russell
AU - Karandish, Sara
AU - Truong, Ronald
AU - Macedo, Amanda B.
AU - Bosque, Alberto
AU - Kovacs, Colin
AU - Benko, Erika
AU - Piechocka-Trocha, Alicja
AU - Wong, Hing
AU - Jeng, Emily
AU - Nixon, Douglas F.
AU - Ho, Ya-Chi
AU - Siliciano, Robert F.
AU - Walker, Bruce D.
AU - Brad Jones, R.
N1 - Funding Information:
This work was supported by grants from the Generation Cure initiative of amfAR (109315-57- RGR); BELIEVE (NIH grant 1UM1AI26617); NIH funded Center for AIDS Research grants (P30 AI060354 and P30 AI117970), which are supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, and OAR; the Mark and Lisa Schwartz Foundation, and NIH R01 AI111860. The following materials were supplied by the NIH AIDS Research and Reference Reagent Program: IL-2, peptides, HIV LAI plasmid J, and MOLT-4 CCR5 cells. We are grateful to Daniel Rosenbloom for helpful discussion related to the design and interpretation of QVOA assays.
Funding Information:
This work was supported by grants from the Generation Cure initiative of amfAR (109315-57-RGR); BELIEVE (NIH grant 1UM1AI26617); NIH funded Center for AIDS Research grants (P30 AI060354 and P30 AI117970), which are supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, and OAR; the Mark and Lisa Schwartz Foundation, and NIH R01 AI111860. The following materials were supplied by the NIH AIDS Research and Reference Reagent Program: IL-2, peptides, HIV LAI plasmid J, and MOLT-4 CCR5 cells. We are grateful to Daniel Rosenbloom for helpful discussion related to the design and interpretation of QVOA assays.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI97555
DO - 10.1172/JCI97555
M3 - Article
C2 - 29355843
AN - SCOPUS:85041481508
SN - 0021-9738
VL - 128
SP - 876
EP - 889
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
ER -