TY - JOUR
T1 - Preferential and persistent impact of acute HIV-1 infection on CD4+ iNKT cells in colonic mucosa
AU - Paquin-Proulx, Dominic
AU - Lal, Kerri G.
AU - Phuang-Ngern, Yuwadee
AU - Creegan, Matthew
AU - Tokarev, Andrey
AU - Suhkumvittaya, Suchada
AU - Alrubayyi, Aljawharah
AU - Kroon, Eugene
AU - Pinyakorn, Suteeraporn
AU - Slike, Bonnie M.
AU - Bolton, Diane L.
AU - Krebs, Shelly J.
AU - Eller, Leigh Anne
AU - Sajjaweerawan, Chayada
AU - Pagliuzza, Amelie
AU - Chomont, Nicolas
AU - Rerknimitr, Rungsun
AU - Chomchey, Nitiya
AU - Phanuphak, Nittaya
AU - de Souza, Mark S.
AU - Michael, Nelson L.
AU - Robb, Merlin L.
AU - Ananworanich, Jintanat
AU - Sandberg, Johan K.
AU - Eller, Michael A.
AU - Schuetz, Alexandra
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank the study participants who committed so much of their time to this study as well as the staff from the Institute of HIV Research and Innovation in Bangkok for their valuable contributions. We also would like to thank the RV217, RV254/SEARCH 010, and RV304/SEARCH 013 study groups. This work was funded by cooperative agreement (W81XWH-18-2-0040) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. and the US Department of Defense (DOD). This research was funded, in part, by the US National Institute of Allergy and Infectious Diseases (Y1-AI-5026-03). RV254 is also supported by an intramural grant from the Thai Red Cross AIDS Research Centre. The ART in RV254 was supported by the Government Pharmaceutical Organization (Thailand), Gilead, Merck, and ViiV Healthcare. The funding source had no role in the study design; collection, analysis, and interpretation of data; writing of the manuscript; or in the decision to publish. This article was prepared while M.A.E. was employed at Henry M. Jackson Foundation for the Advancement of Military Medicine for the US Military HIV Research Program. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of any of the institutions mentioned above, the US Department of the Army or the US DOD, the Henry M. Jackson Foundation for the Advancement of Military Medicine, the NIH, the Department of Health and Human Services, or the US government, nor does the mention of trade names, commercial products, or organizations imply endorsement by the Thai Red Cross AIDS Research Centre. The investigators have adhered to the policies for the protection of human participants as prescribed in AR-70-25.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/11/16
Y1 - 2021/11/16
N2 - Acute HIV-1 infection (AHI) results in the widespread depletion of CD4+ T cells in peripheral blood and gut mucosal tissue. However, the impact on the predominantly CD4+ immunoregulatory invariant natural killer T (iNKT) cells during AHI remains unknown. Here, iNKT cells from peripheral blood and colonic mucosa were investigated during treated and untreated AHI. iNKT cells in blood were activated and rapidly depleted in untreated AHI. At the time of peak HIV-1 viral load, these cells showed the elevated expression of cell death-associated transcripts compared to preinfection. Residual peripheral iNKT cells suffered a diminished responsiveness to in vitro stimulation early into chronic infection. Additionally, HIV-1 DNA, as well as spliced and unspliced viral RNA, were detected in iNKT cells isolated from blood, indicating the active infection of these cells in vivo. The loss of iNKT cells occurred from Fiebig stage III in the colonic mucosa, and these cells were not restored to normal levels after initiation of ART during AHI. CD4+ iNKT cells were depleted faster and more profoundly than conventional CD4+ T cells, and the preferential infection of CD4+ iNKT cells over conventional CD4+ T cells was confirmed by in vitro infection experiments. In vitro data also provided evidence of latent infection in iNKT cells. Strikingly, preinfection levels of peripheral blood CD4+ iNKT cells correlated directly with the peak HIV-1 load. These findings support a model in which iNKT cells are early targets for HIV-1 infection, driving their rapid loss from circulation and colonic mucosa.
AB - Acute HIV-1 infection (AHI) results in the widespread depletion of CD4+ T cells in peripheral blood and gut mucosal tissue. However, the impact on the predominantly CD4+ immunoregulatory invariant natural killer T (iNKT) cells during AHI remains unknown. Here, iNKT cells from peripheral blood and colonic mucosa were investigated during treated and untreated AHI. iNKT cells in blood were activated and rapidly depleted in untreated AHI. At the time of peak HIV-1 viral load, these cells showed the elevated expression of cell death-associated transcripts compared to preinfection. Residual peripheral iNKT cells suffered a diminished responsiveness to in vitro stimulation early into chronic infection. Additionally, HIV-1 DNA, as well as spliced and unspliced viral RNA, were detected in iNKT cells isolated from blood, indicating the active infection of these cells in vivo. The loss of iNKT cells occurred from Fiebig stage III in the colonic mucosa, and these cells were not restored to normal levels after initiation of ART during AHI. CD4+ iNKT cells were depleted faster and more profoundly than conventional CD4+ T cells, and the preferential infection of CD4+ iNKT cells over conventional CD4+ T cells was confirmed by in vitro infection experiments. In vitro data also provided evidence of latent infection in iNKT cells. Strikingly, preinfection levels of peripheral blood CD4+ iNKT cells correlated directly with the peak HIV-1 load. These findings support a model in which iNKT cells are early targets for HIV-1 infection, driving their rapid loss from circulation and colonic mucosa.
KW - ART
KW - Gut
KW - HIV-1
KW - INKT cells
KW - Immune activation
UR - https://www.scopus.com/pages/publications/85119324797
U2 - 10.1073/pnas.2104721118
DO - 10.1073/pnas.2104721118
M3 - Article
C2 - 34753817
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 46
M1 - e2104721118
ER -
SDG 3 Good Health and Well-being