Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption

Meghan K. Rothenberger, Brandon F. Keele, Stephen W. Wietgrefe, Courtney V. Fletcher, Gregory J. Beilman, Jeffrey G. Chipman, Alexander Khoruts, Jacob D. Estes, Jodi Anderson, Samuel P. Callisto, Thomas E. Schmidt, Ann Thorkelson, Cavan Reilly, Katherine Perkey, Thomas G. Reimann, Netanya S. Utay, Krystelle Nganou Makamdop, Mario Stevenson, Daniel C. Douek, Ashley T. Haase & 1 others Timothy W. Schacker

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

Antiretroviral therapy (ART) suppresses HIV replication in most individuals but cannot eradicate latently infected cells established before ART was initiated. Thus, infection rebounds when treatment is interrupted by reactivation of virus production from this reservoir. Currently, one or a few latently infected resting memory CD4 T cells are thought be the principal source of recrudescent infection, but this estimate is based on peripheral blood rather than lymphoid tissues (LTs), the principal sites of virus production and persistence before initiating ART. We, therefore, examined lymph node (LN) and gut-associated lymphoid tissue (GALT) biopsies from fully suppressed subjects, interrupted therapy, monitored plasma viral load (pVL), and repeated biopsies on 12 individuals as soon as pVL became detectable. Isolated HIV RNApositive (vRNA+) cells were detected by in situ hybridization in LTs obtained before interruption in several patients. After interruption, multiple foci of vRNA+ cells were detected in 6 of 12 individuals as soon as pVL was measureable and in some subjects, in more than one anatomic site. Minimal estimates of the number of rebounding/founder (R/F) variants were determined by singlegene amplification and sequencing of viral RNA or DNA from peripheral blood mononuclear cells and plasma obtained at or just before viral recrudescence. Sequence analysis revealed a large number of R/F viruses representing recrudescent viremia from multiple sources. Together, these findings are consistent with the origins of recrudescent infection by reactivation from many latently infected cells at multiple sites. The inferred large pool of cells and sites to rekindle recrudescent infection highlights the challenges in eradicating HIV.

Original languageEnglish (US)
Pages (from-to)E1126-E1134
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number10
DOIs
StatePublished - Mar 10 2015

Fingerprint

Lymphoid Tissue
HIV
Viral Load
Infection
Viruses
Biopsy
Therapeutics
Viremia
Viral DNA
Viral RNA
In Situ Hybridization
Sequence Analysis
Blood Cells
Lymph Nodes
T-Lymphocytes
Recurrence

Keywords

  • Founder population
  • HIV/AIDS
  • Treatment interruption
  • Viral recrudescence

ASJC Scopus subject areas

  • General

Cite this

Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption. / Rothenberger, Meghan K.; Keele, Brandon F.; Wietgrefe, Stephen W.; Fletcher, Courtney V.; Beilman, Gregory J.; Chipman, Jeffrey G.; Khoruts, Alexander; Estes, Jacob D.; Anderson, Jodi; Callisto, Samuel P.; Schmidt, Thomas E.; Thorkelson, Ann; Reilly, Cavan; Perkey, Katherine; Reimann, Thomas G.; Utay, Netanya S.; Makamdop, Krystelle Nganou; Stevenson, Mario; Douek, Daniel C.; Haase, Ashley T.; Schacker, Timothy W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 10, 10.03.2015, p. E1126-E1134.

Research output: Contribution to journalArticle

Rothenberger, MK, Keele, BF, Wietgrefe, SW, Fletcher, CV, Beilman, GJ, Chipman, JG, Khoruts, A, Estes, JD, Anderson, J, Callisto, SP, Schmidt, TE, Thorkelson, A, Reilly, C, Perkey, K, Reimann, TG, Utay, NS, Makamdop, KN, Stevenson, M, Douek, DC, Haase, AT & Schacker, TW 2015, 'Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 10, pp. E1126-E1134. https://doi.org/10.1073/pnas.1414926112
Rothenberger, Meghan K. ; Keele, Brandon F. ; Wietgrefe, Stephen W. ; Fletcher, Courtney V. ; Beilman, Gregory J. ; Chipman, Jeffrey G. ; Khoruts, Alexander ; Estes, Jacob D. ; Anderson, Jodi ; Callisto, Samuel P. ; Schmidt, Thomas E. ; Thorkelson, Ann ; Reilly, Cavan ; Perkey, Katherine ; Reimann, Thomas G. ; Utay, Netanya S. ; Makamdop, Krystelle Nganou ; Stevenson, Mario ; Douek, Daniel C. ; Haase, Ashley T. ; Schacker, Timothy W. / Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 10. pp. E1126-E1134.
@article{2c4e5821d8a14dbba6621d0a82bb3c73,
title = "Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption",
abstract = "Antiretroviral therapy (ART) suppresses HIV replication in most individuals but cannot eradicate latently infected cells established before ART was initiated. Thus, infection rebounds when treatment is interrupted by reactivation of virus production from this reservoir. Currently, one or a few latently infected resting memory CD4 T cells are thought be the principal source of recrudescent infection, but this estimate is based on peripheral blood rather than lymphoid tissues (LTs), the principal sites of virus production and persistence before initiating ART. We, therefore, examined lymph node (LN) and gut-associated lymphoid tissue (GALT) biopsies from fully suppressed subjects, interrupted therapy, monitored plasma viral load (pVL), and repeated biopsies on 12 individuals as soon as pVL became detectable. Isolated HIV RNApositive (vRNA+) cells were detected by in situ hybridization in LTs obtained before interruption in several patients. After interruption, multiple foci of vRNA+ cells were detected in 6 of 12 individuals as soon as pVL was measureable and in some subjects, in more than one anatomic site. Minimal estimates of the number of rebounding/founder (R/F) variants were determined by singlegene amplification and sequencing of viral RNA or DNA from peripheral blood mononuclear cells and plasma obtained at or just before viral recrudescence. Sequence analysis revealed a large number of R/F viruses representing recrudescent viremia from multiple sources. Together, these findings are consistent with the origins of recrudescent infection by reactivation from many latently infected cells at multiple sites. The inferred large pool of cells and sites to rekindle recrudescent infection highlights the challenges in eradicating HIV.",
keywords = "Founder population, HIV/AIDS, Treatment interruption, Viral recrudescence",
author = "Rothenberger, {Meghan K.} and Keele, {Brandon F.} and Wietgrefe, {Stephen W.} and Fletcher, {Courtney V.} and Beilman, {Gregory J.} and Chipman, {Jeffrey G.} and Alexander Khoruts and Estes, {Jacob D.} and Jodi Anderson and Callisto, {Samuel P.} and Schmidt, {Thomas E.} and Ann Thorkelson and Cavan Reilly and Katherine Perkey and Reimann, {Thomas G.} and Utay, {Netanya S.} and Makamdop, {Krystelle Nganou} and Mario Stevenson and Douek, {Daniel C.} and Haase, {Ashley T.} and Schacker, {Timothy W.}",
year = "2015",
month = "3",
day = "10",
doi = "10.1073/pnas.1414926112",
language = "English (US)",
volume = "112",
pages = "E1126--E1134",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "10",

}

TY - JOUR

T1 - Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption

AU - Rothenberger, Meghan K.

AU - Keele, Brandon F.

AU - Wietgrefe, Stephen W.

AU - Fletcher, Courtney V.

AU - Beilman, Gregory J.

AU - Chipman, Jeffrey G.

AU - Khoruts, Alexander

AU - Estes, Jacob D.

AU - Anderson, Jodi

AU - Callisto, Samuel P.

AU - Schmidt, Thomas E.

AU - Thorkelson, Ann

AU - Reilly, Cavan

AU - Perkey, Katherine

AU - Reimann, Thomas G.

AU - Utay, Netanya S.

AU - Makamdop, Krystelle Nganou

AU - Stevenson, Mario

AU - Douek, Daniel C.

AU - Haase, Ashley T.

AU - Schacker, Timothy W.

PY - 2015/3/10

Y1 - 2015/3/10

N2 - Antiretroviral therapy (ART) suppresses HIV replication in most individuals but cannot eradicate latently infected cells established before ART was initiated. Thus, infection rebounds when treatment is interrupted by reactivation of virus production from this reservoir. Currently, one or a few latently infected resting memory CD4 T cells are thought be the principal source of recrudescent infection, but this estimate is based on peripheral blood rather than lymphoid tissues (LTs), the principal sites of virus production and persistence before initiating ART. We, therefore, examined lymph node (LN) and gut-associated lymphoid tissue (GALT) biopsies from fully suppressed subjects, interrupted therapy, monitored plasma viral load (pVL), and repeated biopsies on 12 individuals as soon as pVL became detectable. Isolated HIV RNApositive (vRNA+) cells were detected by in situ hybridization in LTs obtained before interruption in several patients. After interruption, multiple foci of vRNA+ cells were detected in 6 of 12 individuals as soon as pVL was measureable and in some subjects, in more than one anatomic site. Minimal estimates of the number of rebounding/founder (R/F) variants were determined by singlegene amplification and sequencing of viral RNA or DNA from peripheral blood mononuclear cells and plasma obtained at or just before viral recrudescence. Sequence analysis revealed a large number of R/F viruses representing recrudescent viremia from multiple sources. Together, these findings are consistent with the origins of recrudescent infection by reactivation from many latently infected cells at multiple sites. The inferred large pool of cells and sites to rekindle recrudescent infection highlights the challenges in eradicating HIV.

AB - Antiretroviral therapy (ART) suppresses HIV replication in most individuals but cannot eradicate latently infected cells established before ART was initiated. Thus, infection rebounds when treatment is interrupted by reactivation of virus production from this reservoir. Currently, one or a few latently infected resting memory CD4 T cells are thought be the principal source of recrudescent infection, but this estimate is based on peripheral blood rather than lymphoid tissues (LTs), the principal sites of virus production and persistence before initiating ART. We, therefore, examined lymph node (LN) and gut-associated lymphoid tissue (GALT) biopsies from fully suppressed subjects, interrupted therapy, monitored plasma viral load (pVL), and repeated biopsies on 12 individuals as soon as pVL became detectable. Isolated HIV RNApositive (vRNA+) cells were detected by in situ hybridization in LTs obtained before interruption in several patients. After interruption, multiple foci of vRNA+ cells were detected in 6 of 12 individuals as soon as pVL was measureable and in some subjects, in more than one anatomic site. Minimal estimates of the number of rebounding/founder (R/F) variants were determined by singlegene amplification and sequencing of viral RNA or DNA from peripheral blood mononuclear cells and plasma obtained at or just before viral recrudescence. Sequence analysis revealed a large number of R/F viruses representing recrudescent viremia from multiple sources. Together, these findings are consistent with the origins of recrudescent infection by reactivation from many latently infected cells at multiple sites. The inferred large pool of cells and sites to rekindle recrudescent infection highlights the challenges in eradicating HIV.

KW - Founder population

KW - HIV/AIDS

KW - Treatment interruption

KW - Viral recrudescence

UR - http://www.scopus.com/inward/record.url?scp=84924365877&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924365877&partnerID=8YFLogxK

U2 - 10.1073/pnas.1414926112

DO - 10.1073/pnas.1414926112

M3 - Article

VL - 112

SP - E1126-E1134

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

SN - 0027-8424

IS - 10

ER -