HIV-1 persistence following extre277277mely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study

Timothy J. Henrich, Hiroyu Hatano, Oliver Bacon, Louise E. Hogan, Rachel Rutishauser, Alison Hill, Mary F. Kearney, Elizabeth M. Anderson, Susan P. Buchbinder, Stephanie E. Cohen, Mohamed Abdel-Mohsen, Christopher W. Pohlmeyer, Remi Fromentin, Rebecca Hoh, Albert Y. Liu, Joseph M. McCune, Jonathan Spindler, Kelly Pate, Kristen S. Hobbs, Cassandra ThanhErica A. Gibson, Daniel R. Kuritzkes, Robert F Siliciano, Richard W. Price, Douglas D. Richman, Nicolas Chomont, Janet M Siliciano, John W. Mellors, Steven A. Yukl, Joel N Blankson, Teri Liegler, Steven G. Deeks

Research output: Contribution to journalArticle

Abstract

Background: It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART. Methods and findings: Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection. Conclusions: We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.

Original languageEnglish (US)
Article numbere1002417
JournalPLoS Medicine
Volume14
Issue number11
DOIs
StatePublished - Nov 1 2017

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HIV Infections
Observational Studies
HIV-1
HIV
RNA
Therapeutics
Viremia
Tenofovir
T-Lymphocyte Subsets
Infection
T-Lymphocytes
Lymph Nodes
Bone Marrow
Pre-Exposure Prophylaxis
Tumor Biomarkers
Viral Load
Ileum
Rectum
Sample Size
Blood Cells

ASJC Scopus subject areas

  • Medicine(all)

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HIV-1 persistence following extre277277mely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection : An observational study. / Henrich, Timothy J.; Hatano, Hiroyu; Bacon, Oliver; Hogan, Louise E.; Rutishauser, Rachel; Hill, Alison; Kearney, Mary F.; Anderson, Elizabeth M.; Buchbinder, Susan P.; Cohen, Stephanie E.; Abdel-Mohsen, Mohamed; Pohlmeyer, Christopher W.; Fromentin, Remi; Hoh, Rebecca; Liu, Albert Y.; McCune, Joseph M.; Spindler, Jonathan; Pate, Kelly; Hobbs, Kristen S.; Thanh, Cassandra; Gibson, Erica A.; Kuritzkes, Daniel R.; Siliciano, Robert F; Price, Richard W.; Richman, Douglas D.; Chomont, Nicolas; Siliciano, Janet M; Mellors, John W.; Yukl, Steven A.; Blankson, Joel N; Liegler, Teri; Deeks, Steven G.

In: PLoS Medicine, Vol. 14, No. 11, e1002417, 01.11.2017.

Research output: Contribution to journalArticle

Henrich, TJ, Hatano, H, Bacon, O, Hogan, LE, Rutishauser, R, Hill, A, Kearney, MF, Anderson, EM, Buchbinder, SP, Cohen, SE, Abdel-Mohsen, M, Pohlmeyer, CW, Fromentin, R, Hoh, R, Liu, AY, McCune, JM, Spindler, J, Pate, K, Hobbs, KS, Thanh, C, Gibson, EA, Kuritzkes, DR, Siliciano, RF, Price, RW, Richman, DD, Chomont, N, Siliciano, JM, Mellors, JW, Yukl, SA, Blankson, JN, Liegler, T & Deeks, SG 2017, 'HIV-1 persistence following extre277277mely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study', PLoS Medicine, vol. 14, no. 11, e1002417. https://doi.org/10.1371/journal.pmed.1002417
Henrich, Timothy J. ; Hatano, Hiroyu ; Bacon, Oliver ; Hogan, Louise E. ; Rutishauser, Rachel ; Hill, Alison ; Kearney, Mary F. ; Anderson, Elizabeth M. ; Buchbinder, Susan P. ; Cohen, Stephanie E. ; Abdel-Mohsen, Mohamed ; Pohlmeyer, Christopher W. ; Fromentin, Remi ; Hoh, Rebecca ; Liu, Albert Y. ; McCune, Joseph M. ; Spindler, Jonathan ; Pate, Kelly ; Hobbs, Kristen S. ; Thanh, Cassandra ; Gibson, Erica A. ; Kuritzkes, Daniel R. ; Siliciano, Robert F ; Price, Richard W. ; Richman, Douglas D. ; Chomont, Nicolas ; Siliciano, Janet M ; Mellors, John W. ; Yukl, Steven A. ; Blankson, Joel N ; Liegler, Teri ; Deeks, Steven G. / HIV-1 persistence following extre277277mely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection : An observational study. In: PLoS Medicine. 2017 ; Vol. 14, No. 11.
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abstract = "Background: It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART. Methods and findings: Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1{\%} of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection. Conclusions: We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.",
author = "Henrich, {Timothy J.} and Hiroyu Hatano and Oliver Bacon and Hogan, {Louise E.} and Rachel Rutishauser and Alison Hill and Kearney, {Mary F.} and Anderson, {Elizabeth M.} and Buchbinder, {Susan P.} and Cohen, {Stephanie E.} and Mohamed Abdel-Mohsen and Pohlmeyer, {Christopher W.} and Remi Fromentin and Rebecca Hoh and Liu, {Albert Y.} and McCune, {Joseph M.} and Jonathan Spindler and Kelly Pate and Hobbs, {Kristen S.} and Cassandra Thanh and Gibson, {Erica A.} and Kuritzkes, {Daniel R.} and Siliciano, {Robert F} and Price, {Richard W.} and Richman, {Douglas D.} and Nicolas Chomont and Siliciano, {Janet M} and Mellors, {John W.} and Yukl, {Steven A.} and Blankson, {Joel N} and Teri Liegler and Deeks, {Steven G.}",
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TY - JOUR

T1 - HIV-1 persistence following extre277277mely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection

T2 - An observational study

AU - Henrich, Timothy J.

AU - Hatano, Hiroyu

AU - Bacon, Oliver

AU - Hogan, Louise E.

AU - Rutishauser, Rachel

AU - Hill, Alison

AU - Kearney, Mary F.

AU - Anderson, Elizabeth M.

AU - Buchbinder, Susan P.

AU - Cohen, Stephanie E.

AU - Abdel-Mohsen, Mohamed

AU - Pohlmeyer, Christopher W.

AU - Fromentin, Remi

AU - Hoh, Rebecca

AU - Liu, Albert Y.

AU - McCune, Joseph M.

AU - Spindler, Jonathan

AU - Pate, Kelly

AU - Hobbs, Kristen S.

AU - Thanh, Cassandra

AU - Gibson, Erica A.

AU - Kuritzkes, Daniel R.

AU - Siliciano, Robert F

AU - Price, Richard W.

AU - Richman, Douglas D.

AU - Chomont, Nicolas

AU - Siliciano, Janet M

AU - Mellors, John W.

AU - Yukl, Steven A.

AU - Blankson, Joel N

AU - Liegler, Teri

AU - Deeks, Steven G.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Background: It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART. Methods and findings: Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection. Conclusions: We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.

AB - Background: It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART. Methods and findings: Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection. Conclusions: We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.

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