Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption
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 laten...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Mario Stevenson [verfasserIn] |
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| Format: |
Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2015 |
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| Rechteinformationen: |
Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences |
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| Schlagwörter: |
Anti-HIV Agents - therapeutic use Anti-HIV Agents - administration & dosage |
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| Übergeordnetes Werk: |
Enthalten in: Proceedings of the National Academy of Sciences of the United States of America - Washington, DC : NAS, 1877, 112(2015), 10, Seite E1126-E1134 |
|---|---|
| Übergeordnetes Werk: |
volume:112 ; year:2015 ; number:10 ; pages:E1126-E1134 |
| Links: |
Volltext |
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| DOI / URN: |
10.1073/pnas.1414926112 |
|---|
| Katalog-ID: |
OLC1970259973 |
|---|
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| 245 | 1 | 0 | |a Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption |
| 264 | 1 | |c 2015 | |
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| 520 | |a 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 RNA-positive (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 single-gene 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. | ||
| 540 | |a Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences | ||
| 650 | 4 | |a HIV - physiology | |
| 650 | 4 | |a RNA, Viral - blood | |
| 650 | 4 | |a HIV - genetics | |
| 650 | 4 | |a HIV Infections - virology | |
| 650 | 4 | |a Lymphoid Tissue - virology | |
| 650 | 4 | |a Anti-HIV Agents - therapeutic use | |
| 650 | 4 | |a Anti-HIV Agents - administration & dosage | |
| 650 | 4 | |a HIV Infections - drug therapy | |
| 650 | 4 | |a Antiviral agents | |
| 650 | 4 | |a Drug therapy | |
| 650 | 4 | |a Dosage and administration | |
| 650 | 4 | |a Observations | |
| 650 | 4 | |a HIV infection | |
| 650 | 4 | |a Genetic variation | |
| 650 | 4 | |a Genetic aspects | |
| 650 | 4 | |a Tissue | |
| 650 | 4 | |a Human immunodeficiency virus--HIV | |
| 650 | 4 | |a Antiretroviral drugs | |
| 650 | 4 | |a Cells | |
| 650 | 4 | |a Lymphatic system | |
| 650 | 4 | |a PNAS Plus | |
| 650 | 4 | |a founder population | |
| 650 | 4 | |a AIDS | |
| 650 | 4 | |a treatment interruption | |
| 650 | 4 | |a HIV | |
| 650 | 4 | |a Biological Sciences | |
| 650 | 4 | |a viral recrudescence | |
| 700 | 0 | |a Ann Thorkelson |4 oth | |
| 700 | 0 | |a Jeffrey G. Chipman |4 oth | |
| 700 | 0 | |a Timothy W. Schacker |4 oth | |
| 700 | 0 | |a Samuel P. Callisto |4 oth | |
| 700 | 0 | |a Alexander Khoruts |4 oth | |
| 700 | 0 | |a Cavan Reilly |4 oth | |
| 700 | 0 | |a Brandon F. Keele |4 oth | |
| 700 | 0 | |a Netanya S. Utay |4 oth | |
| 700 | 0 | |a Ashley T. Haase |4 oth | |
| 700 | 0 | |a Jacob D. Estes |4 oth | |
| 700 | 0 | |a Stephen W. Wietgrefe |4 oth | |
| 700 | 0 | |a Courtney V. Fletcher |4 oth | |
| 700 | 0 | |a Thomas E. Schmidt |4 oth | |
| 700 | 0 | |a Krystelle Nganou Makamdop |4 oth | |
| 700 | 0 | |a Meghan K. Rothenberger |4 oth | |
| 700 | 0 | |a Daniel C. Douek |4 oth | |
| 700 | 0 | |a Thomas G. Reimann |4 oth | |
| 700 | 0 | |a Gregory J. Beilman |4 oth | |
| 700 | 0 | |a Jodi Anderson |4 oth | |
| 700 | 0 | |a Katherine Perkey |4 oth | |
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| 856 | 4 | 1 | |u http://dx.doi.org/10.1073/pnas.1414926112 |3 Volltext |
| 856 | 4 | 2 | |u http://www.pnas.org/content/112/10/E1126.abstract |
| 856 | 4 | 2 | |u http://www.ncbi.nlm.nih.gov/pubmed/25713386 |
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10.1073/pnas.1414926112 doi PQ20160211 (DE-627)OLC1970259973 (DE-599)GBVOLC1970259973 (PRQ)c3062-a90f892c1b7071581f7aadfe480da69975608fa69c969c4564ac7fe2076ae5cb3 (KEY)0583363920150000112001001126largenumberofreboundingfounderhivvariantsemergefro DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Mario Stevenson verfasserin aut Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier 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 RNA-positive (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 single-gene 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. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences HIV - physiology RNA, Viral - blood HIV - genetics HIV Infections - virology Lymphoid Tissue - virology Anti-HIV Agents - therapeutic use Anti-HIV Agents - administration & dosage HIV Infections - drug therapy Antiviral agents Drug therapy Dosage and administration Observations HIV infection Genetic variation Genetic aspects Tissue Human immunodeficiency virus--HIV Antiretroviral drugs Cells Lymphatic system PNAS Plus founder population AIDS treatment interruption HIV Biological Sciences viral recrudescence Ann Thorkelson oth Jeffrey G. Chipman oth Timothy W. Schacker oth Samuel P. Callisto oth Alexander Khoruts oth Cavan Reilly oth Brandon F. Keele oth Netanya S. Utay oth Ashley T. Haase oth Jacob D. Estes oth Stephen W. Wietgrefe oth Courtney V. Fletcher oth Thomas E. Schmidt oth Krystelle Nganou Makamdop oth Meghan K. Rothenberger oth Daniel C. Douek oth Thomas G. Reimann oth Gregory J. Beilman oth Jodi Anderson oth Katherine Perkey oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 10, Seite E1126-E1134 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:10 pages:E1126-E1134 http://dx.doi.org/10.1073/pnas.1414926112 Volltext http://www.pnas.org/content/112/10/E1126.abstract http://www.ncbi.nlm.nih.gov/pubmed/25713386 http://search.proquest.com/docview/1663918856 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4364237&tool=pmcentrez&rendertype=abstract GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 10 E1126-E1134 |
| spelling |
10.1073/pnas.1414926112 doi PQ20160211 (DE-627)OLC1970259973 (DE-599)GBVOLC1970259973 (PRQ)c3062-a90f892c1b7071581f7aadfe480da69975608fa69c969c4564ac7fe2076ae5cb3 (KEY)0583363920150000112001001126largenumberofreboundingfounderhivvariantsemergefro DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Mario Stevenson verfasserin aut Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier 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 RNA-positive (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 single-gene 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. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences HIV - physiology RNA, Viral - blood HIV - genetics HIV Infections - virology Lymphoid Tissue - virology Anti-HIV Agents - therapeutic use Anti-HIV Agents - administration & dosage HIV Infections - drug therapy Antiviral agents Drug therapy Dosage and administration Observations HIV infection Genetic variation Genetic aspects Tissue Human immunodeficiency virus--HIV Antiretroviral drugs Cells Lymphatic system PNAS Plus founder population AIDS treatment interruption HIV Biological Sciences viral recrudescence Ann Thorkelson oth Jeffrey G. Chipman oth Timothy W. Schacker oth Samuel P. Callisto oth Alexander Khoruts oth Cavan Reilly oth Brandon F. Keele oth Netanya S. Utay oth Ashley T. Haase oth Jacob D. Estes oth Stephen W. Wietgrefe oth Courtney V. Fletcher oth Thomas E. Schmidt oth Krystelle Nganou Makamdop oth Meghan K. Rothenberger oth Daniel C. Douek oth Thomas G. Reimann oth Gregory J. Beilman oth Jodi Anderson oth Katherine Perkey oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 10, Seite E1126-E1134 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:10 pages:E1126-E1134 http://dx.doi.org/10.1073/pnas.1414926112 Volltext http://www.pnas.org/content/112/10/E1126.abstract http://www.ncbi.nlm.nih.gov/pubmed/25713386 http://search.proquest.com/docview/1663918856 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4364237&tool=pmcentrez&rendertype=abstract GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 10 E1126-E1134 |
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10.1073/pnas.1414926112 doi PQ20160211 (DE-627)OLC1970259973 (DE-599)GBVOLC1970259973 (PRQ)c3062-a90f892c1b7071581f7aadfe480da69975608fa69c969c4564ac7fe2076ae5cb3 (KEY)0583363920150000112001001126largenumberofreboundingfounderhivvariantsemergefro DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Mario Stevenson verfasserin aut Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier 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 RNA-positive (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 single-gene 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. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences HIV - physiology RNA, Viral - blood HIV - genetics HIV Infections - virology Lymphoid Tissue - virology Anti-HIV Agents - therapeutic use Anti-HIV Agents - administration & dosage HIV Infections - drug therapy Antiviral agents Drug therapy Dosage and administration Observations HIV infection Genetic variation Genetic aspects Tissue Human immunodeficiency virus--HIV Antiretroviral drugs Cells Lymphatic system PNAS Plus founder population AIDS treatment interruption HIV Biological Sciences viral recrudescence Ann Thorkelson oth Jeffrey G. Chipman oth Timothy W. Schacker oth Samuel P. Callisto oth Alexander Khoruts oth Cavan Reilly oth Brandon F. Keele oth Netanya S. Utay oth Ashley T. Haase oth Jacob D. Estes oth Stephen W. Wietgrefe oth Courtney V. Fletcher oth Thomas E. Schmidt oth Krystelle Nganou Makamdop oth Meghan K. Rothenberger oth Daniel C. Douek oth Thomas G. Reimann oth Gregory J. Beilman oth Jodi Anderson oth Katherine Perkey oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 10, Seite E1126-E1134 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:10 pages:E1126-E1134 http://dx.doi.org/10.1073/pnas.1414926112 Volltext http://www.pnas.org/content/112/10/E1126.abstract http://www.ncbi.nlm.nih.gov/pubmed/25713386 http://search.proquest.com/docview/1663918856 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4364237&tool=pmcentrez&rendertype=abstract GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 10 E1126-E1134 |
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10.1073/pnas.1414926112 doi PQ20160211 (DE-627)OLC1970259973 (DE-599)GBVOLC1970259973 (PRQ)c3062-a90f892c1b7071581f7aadfe480da69975608fa69c969c4564ac7fe2076ae5cb3 (KEY)0583363920150000112001001126largenumberofreboundingfounderhivvariantsemergefro DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Mario Stevenson verfasserin aut Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier 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 RNA-positive (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 single-gene 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. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences HIV - physiology RNA, Viral - blood HIV - genetics HIV Infections - virology Lymphoid Tissue - virology Anti-HIV Agents - therapeutic use Anti-HIV Agents - administration & dosage HIV Infections - drug therapy Antiviral agents Drug therapy Dosage and administration Observations HIV infection Genetic variation Genetic aspects Tissue Human immunodeficiency virus--HIV Antiretroviral drugs Cells Lymphatic system PNAS Plus founder population AIDS treatment interruption HIV Biological Sciences viral recrudescence Ann Thorkelson oth Jeffrey G. Chipman oth Timothy W. Schacker oth Samuel P. Callisto oth Alexander Khoruts oth Cavan Reilly oth Brandon F. Keele oth Netanya S. Utay oth Ashley T. Haase oth Jacob D. Estes oth Stephen W. Wietgrefe oth Courtney V. Fletcher oth Thomas E. Schmidt oth Krystelle Nganou Makamdop oth Meghan K. Rothenberger oth Daniel C. Douek oth Thomas G. Reimann oth Gregory J. Beilman oth Jodi Anderson oth Katherine Perkey oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 10, Seite E1126-E1134 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:10 pages:E1126-E1134 http://dx.doi.org/10.1073/pnas.1414926112 Volltext http://www.pnas.org/content/112/10/E1126.abstract http://www.ncbi.nlm.nih.gov/pubmed/25713386 http://search.proquest.com/docview/1663918856 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4364237&tool=pmcentrez&rendertype=abstract GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 10 E1126-E1134 |
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Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption |
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Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption |
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large number of rebounding/founder hiv variants emerge from multifocal infection in lymphatic tissues after treatment interruption |
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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 RNA-positive (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 single-gene 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. |
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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 RNA-positive (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 single-gene 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. |
| abstract_unstemmed |
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 RNA-positive (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 single-gene 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. |
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Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption |
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Ann Thorkelson Jeffrey G. Chipman Timothy W. Schacker Samuel P. Callisto Alexander Khoruts Cavan Reilly Brandon F. Keele Netanya S. Utay Ashley T. Haase Jacob D. Estes Stephen W. Wietgrefe Courtney V. Fletcher Thomas E. Schmidt Krystelle Nganou Makamdop Meghan K. Rothenberger Daniel C. Douek Thomas G. Reimann Gregory J. Beilman Jodi Anderson Katherine Perkey |
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