TY - JOUR
T1 - HIV-1 proviral landscapes distinguish posttreatment controllers from noncontrollers
AU - Sharaf, Radwa
AU - Lee, Guinevere Q.
AU - Sun, Xiaoming
AU - Etemad, Behzad
AU - Aboukhater, Layla M.
AU - Hu, Zixin
AU - Brumme, Zabrina L.
AU - Aga, Evgenia
AU - Bosch, Ronald J.
AU - Wen, Ying
AU - Namazi, Golnaz
AU - Gao, Ce
AU - Acosta, Edward P.
AU - Gandhi, Rajesh T.
AU - Jacobson, Jeffrey M.
AU - Skiest, Daniel
AU - Margolis, David M.
AU - Mitsuyasu, Ronald
AU - Volberding, Paul
AU - Connick, Elizabeth
AU - Kuritzkes, Daniel R.
AU - Lederman, Michael M.
AU - Yu, Xu G.
AU - Lichterfeld, Mathias
AU - Li, Jonathan Z.
N1 - Funding Information:
Conflict of interest: JZL has received research support and consulted for Gilead and Merck. RTG has received educational grants from Gilead, Merck, and ViiV. DRK serves as a consultant to and/or has received research support from Gilead, Janssen, Merck, and ViiV. DS has received research support from Gilead, ViiV, and GlaxoSmithKline. MML has received research support from Gilead. Submitted: February 15, 2018; Accepted: July 3, 2018. Reference information: J Clin Invest. 2018;128(9):4074–4085. https://doi.org/10.1172/JCI120549.
Funding Information:
This work was supported in part by National Institutes of Health/ National Institute of Allergy and Infectious Diseases grants: AI125109 (to JZL), the Harvard University Center for AIDS Research (5P30AI060354-08 to JZL and RTG, 5P30AI060354-14 to GQL), UM1AI068634 (Statistical and Data Management Center of the AIDS Clinical Trials Group), UM1AI068636 (AIDS Clinical Trials Group), a subcontract from UM1AI106701 to the Harvard Virology Support Laboratory (to JZL), UM1AI126617 (to ZLB and EC), and UM1AI069423 (to DM). ZLB is supported by a Scholar Award from the Michael Smith Foundation for Health Research. We are grateful for the contributions of the participants who made this study possible. We thank the staff and principal investigators of ACTG studies A371, A5024, A5068, A5170, and A5197. We appreciate the support of Nicole Stange-Thomann and the staff of the MGH sequencing core facility. We thank Wei-Shau Hu, Tsibris, and Kuritzkes labs for valuable feedback.
Publisher Copyright:
© 2018 American Society for Clinical Investigation. All rights reserved.
PY - 2018/8/31
Y1 - 2018/8/31
N2 - HIV posttreatment controllers (PTCs) represent a natural model of sustained HIV remission, but they are rare and little is known about their viral reservoir. We obtained 1,450 proviral sequences after near-full-length amplification for 10 PTCs and 16 posttreatment noncontrollers (NCs). Before treatment interruption, the median intact and total reservoir size in PTCs was 7-fold lower than in NCs, but the proportion of intact, defective, and total clonally expanded proviral genomes was not significantly different between the 2 groups. Quantification of total but not intact proviral genome copies predicted sustained HIV remission as 81% of NCs, but none of the PTCs had a total proviral genome greater than 4 copies per million peripheral blood mononuclear cells (PBMCs). The results highlight the restricted intact and defective HIV reservoir in PTCs and suggest that total proviral genome burden could act as the first biomarker for identifying PTCs. Total and defective but not intact proviral copy numbers correlated with levels of cell-associated HIV RNA, activated NK cell percentages, and both HIV-specific CD4+ and CD8+ responses. These results support the concept that defective HIV genomes can lead to viral antigen production and interact with both the innate and adaptive immune systems.
AB - HIV posttreatment controllers (PTCs) represent a natural model of sustained HIV remission, but they are rare and little is known about their viral reservoir. We obtained 1,450 proviral sequences after near-full-length amplification for 10 PTCs and 16 posttreatment noncontrollers (NCs). Before treatment interruption, the median intact and total reservoir size in PTCs was 7-fold lower than in NCs, but the proportion of intact, defective, and total clonally expanded proviral genomes was not significantly different between the 2 groups. Quantification of total but not intact proviral genome copies predicted sustained HIV remission as 81% of NCs, but none of the PTCs had a total proviral genome greater than 4 copies per million peripheral blood mononuclear cells (PBMCs). The results highlight the restricted intact and defective HIV reservoir in PTCs and suggest that total proviral genome burden could act as the first biomarker for identifying PTCs. Total and defective but not intact proviral copy numbers correlated with levels of cell-associated HIV RNA, activated NK cell percentages, and both HIV-specific CD4+ and CD8+ responses. These results support the concept that defective HIV genomes can lead to viral antigen production and interact with both the innate and adaptive immune systems.
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U2 - 10.1172/JCI120549
DO - 10.1172/JCI120549
M3 - Article
C2 - 30024859
AN - SCOPUS:85052552996
VL - 128
SP - 4074
EP - 4085
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 9
ER -