Extensive virologic and immunologic characterization in an HIV-infected individual following allogeneic stem cell transplant and analytic cessation of antiretroviral therapy: A case study

Nathan W Cummins, Stacey Rizza, Mark R Litzow, Stephane Hua, Guinevere Q. Lee, Kevin Einkauf, Tae Wook Chun, Frank Rhame, Jason V. Baker, Michael P. Busch, Nicolas Chomont, Patrick G. Dean, Rémi Fromentin, Ashley T. Haase, Dylan Hampton, Sheila M. Keating, Steven M. Lada, Tzong Hae Lee, Sekar Natesampillai, Douglas D. RichmanTimothy W. Schacker, Stephen Wietgrefe, Xu G. Yu, Joseph D. Yao, John Zeuli, Mathias Lichterfeld, Andrew David Badley

Research output: Contribution to journalArticle

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Abstract

Background: Notwithstanding 1 documented case of HIV-1 cure following allogeneic stem cell transplantation (allo-SCT), several subsequent cases of allo-SCT in HIV-1 positive individuals have failed to cure HIV-1 infection. The aim of our study was to describe changes in the HIV reservoir in a single chronically HIV-infected patient on suppressive antiretroviral therapy who underwent allo-SCT for treatment of acute lymphoblastic leukemia. Methods and findings: We prospectively collected peripheral blood mononuclear cells (PBMCs) by leukapheresis from a 55-year-old man with chronic HIV infection before and after allo-SCT to measure the size of the HIV-1 reservoir and characterize viral phylogeny and phenotypic changes in immune cells. At day 784 post-transplant, when HIV-1 was undetectable by multiple measures—including PCR measurements of both total and integrated HIV-1 DNA, replication-competent virus measurement by large cell input quantitative viral outgrowth assay, and in situ hybridization of colon tissue—the patient consented to an analytic treatment interruption (ATI) with frequent clinical monitoring. He remained aviremic off antiretroviral therapy until ATI day 288, when a low-level virus rebound of 60 HIV-1 copies/ml occurred, which increased to 1,640 HIV-1 copies/ml 5 days later, prompting reinitiation of ART. Rebounding plasma HIV-1 sequences were phylogenetically distinct from proviral HIV-1 DNA detected in circulating PBMCs before transplantation. The main limitations of this study are the insensitivity of reservoir measurements, and the fact that it describes a single case. Conclusions: allo-SCT led to a significant reduction in the size of the HIV-1 reservoir and a >9-month-long ART-free remission from HIV-1 replication. Phylogenetic analyses suggest that the origin of rebound virus was distinct from the viruses identified pre-transplant in the PBMCs.

Original languageEnglish (US)
Article numbere1002461
JournalPLoS Medicine
Volume14
Issue number11
DOIs
StatePublished - Nov 1 2017

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HIV-1
Stem Cells
HIV
Transplants
Stem Cell Transplantation
Therapeutics
Viruses
Blood Cells
HIV Infections
Leukapheresis
Cell Transplantation
Phylogeny
DNA Replication
Precursor Cell Lymphoblastic Leukemia-Lymphoma
In Situ Hybridization
Colon
Polymerase Chain Reaction
DNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Extensive virologic and immunologic characterization in an HIV-infected individual following allogeneic stem cell transplant and analytic cessation of antiretroviral therapy : A case study. / Cummins, Nathan W; Rizza, Stacey; Litzow, Mark R; Hua, Stephane; Lee, Guinevere Q.; Einkauf, Kevin; Chun, Tae Wook; Rhame, Frank; Baker, Jason V.; Busch, Michael P.; Chomont, Nicolas; Dean, Patrick G.; Fromentin, Rémi; Haase, Ashley T.; Hampton, Dylan; Keating, Sheila M.; Lada, Steven M.; Lee, Tzong Hae; Natesampillai, Sekar; Richman, Douglas D.; Schacker, Timothy W.; Wietgrefe, Stephen; Yu, Xu G.; Yao, Joseph D.; Zeuli, John; Lichterfeld, Mathias; Badley, Andrew David.

In: PLoS Medicine, Vol. 14, No. 11, e1002461, 01.11.2017.

Research output: Contribution to journalArticle

Cummins, NW, Rizza, S, Litzow, MR, Hua, S, Lee, GQ, Einkauf, K, Chun, TW, Rhame, F, Baker, JV, Busch, MP, Chomont, N, Dean, PG, Fromentin, R, Haase, AT, Hampton, D, Keating, SM, Lada, SM, Lee, TH, Natesampillai, S, Richman, DD, Schacker, TW, Wietgrefe, S, Yu, XG, Yao, JD, Zeuli, J, Lichterfeld, M & Badley, AD 2017, 'Extensive virologic and immunologic characterization in an HIV-infected individual following allogeneic stem cell transplant and analytic cessation of antiretroviral therapy: A case study', PLoS Medicine, vol. 14, no. 11, e1002461. https://doi.org/10.1371/journal.pmed.1002461
Cummins, Nathan W ; Rizza, Stacey ; Litzow, Mark R ; Hua, Stephane ; Lee, Guinevere Q. ; Einkauf, Kevin ; Chun, Tae Wook ; Rhame, Frank ; Baker, Jason V. ; Busch, Michael P. ; Chomont, Nicolas ; Dean, Patrick G. ; Fromentin, Rémi ; Haase, Ashley T. ; Hampton, Dylan ; Keating, Sheila M. ; Lada, Steven M. ; Lee, Tzong Hae ; Natesampillai, Sekar ; Richman, Douglas D. ; Schacker, Timothy W. ; Wietgrefe, Stephen ; Yu, Xu G. ; Yao, Joseph D. ; Zeuli, John ; Lichterfeld, Mathias ; Badley, Andrew David. / Extensive virologic and immunologic characterization in an HIV-infected individual following allogeneic stem cell transplant and analytic cessation of antiretroviral therapy : A case study. In: PLoS Medicine. 2017 ; Vol. 14, No. 11.
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abstract = "Background: Notwithstanding 1 documented case of HIV-1 cure following allogeneic stem cell transplantation (allo-SCT), several subsequent cases of allo-SCT in HIV-1 positive individuals have failed to cure HIV-1 infection. The aim of our study was to describe changes in the HIV reservoir in a single chronically HIV-infected patient on suppressive antiretroviral therapy who underwent allo-SCT for treatment of acute lymphoblastic leukemia. Methods and findings: We prospectively collected peripheral blood mononuclear cells (PBMCs) by leukapheresis from a 55-year-old man with chronic HIV infection before and after allo-SCT to measure the size of the HIV-1 reservoir and characterize viral phylogeny and phenotypic changes in immune cells. At day 784 post-transplant, when HIV-1 was undetectable by multiple measures—including PCR measurements of both total and integrated HIV-1 DNA, replication-competent virus measurement by large cell input quantitative viral outgrowth assay, and in situ hybridization of colon tissue—the patient consented to an analytic treatment interruption (ATI) with frequent clinical monitoring. He remained aviremic off antiretroviral therapy until ATI day 288, when a low-level virus rebound of 60 HIV-1 copies/ml occurred, which increased to 1,640 HIV-1 copies/ml 5 days later, prompting reinitiation of ART. Rebounding plasma HIV-1 sequences were phylogenetically distinct from proviral HIV-1 DNA detected in circulating PBMCs before transplantation. The main limitations of this study are the insensitivity of reservoir measurements, and the fact that it describes a single case. Conclusions: allo-SCT led to a significant reduction in the size of the HIV-1 reservoir and a >9-month-long ART-free remission from HIV-1 replication. Phylogenetic analyses suggest that the origin of rebound virus was distinct from the viruses identified pre-transplant in the PBMCs.",
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T2 - A case study

AU - Cummins, Nathan W

AU - Rizza, Stacey

AU - Litzow, Mark R

AU - Hua, Stephane

AU - Lee, Guinevere Q.

AU - Einkauf, Kevin

AU - Chun, Tae Wook

AU - Rhame, Frank

AU - Baker, Jason V.

AU - Busch, Michael P.

AU - Chomont, Nicolas

AU - Dean, Patrick G.

AU - Fromentin, Rémi

AU - Haase, Ashley T.

AU - Hampton, Dylan

AU - Keating, Sheila M.

AU - Lada, Steven M.

AU - Lee, Tzong Hae

AU - Natesampillai, Sekar

AU - Richman, Douglas D.

AU - Schacker, Timothy W.

AU - Wietgrefe, Stephen

AU - Yu, Xu G.

AU - Yao, Joseph D.

AU - Zeuli, John

AU - Lichterfeld, Mathias

AU - Badley, Andrew David

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N2 - Background: Notwithstanding 1 documented case of HIV-1 cure following allogeneic stem cell transplantation (allo-SCT), several subsequent cases of allo-SCT in HIV-1 positive individuals have failed to cure HIV-1 infection. The aim of our study was to describe changes in the HIV reservoir in a single chronically HIV-infected patient on suppressive antiretroviral therapy who underwent allo-SCT for treatment of acute lymphoblastic leukemia. Methods and findings: We prospectively collected peripheral blood mononuclear cells (PBMCs) by leukapheresis from a 55-year-old man with chronic HIV infection before and after allo-SCT to measure the size of the HIV-1 reservoir and characterize viral phylogeny and phenotypic changes in immune cells. At day 784 post-transplant, when HIV-1 was undetectable by multiple measures—including PCR measurements of both total and integrated HIV-1 DNA, replication-competent virus measurement by large cell input quantitative viral outgrowth assay, and in situ hybridization of colon tissue—the patient consented to an analytic treatment interruption (ATI) with frequent clinical monitoring. He remained aviremic off antiretroviral therapy until ATI day 288, when a low-level virus rebound of 60 HIV-1 copies/ml occurred, which increased to 1,640 HIV-1 copies/ml 5 days later, prompting reinitiation of ART. Rebounding plasma HIV-1 sequences were phylogenetically distinct from proviral HIV-1 DNA detected in circulating PBMCs before transplantation. The main limitations of this study are the insensitivity of reservoir measurements, and the fact that it describes a single case. Conclusions: allo-SCT led to a significant reduction in the size of the HIV-1 reservoir and a >9-month-long ART-free remission from HIV-1 replication. Phylogenetic analyses suggest that the origin of rebound virus was distinct from the viruses identified pre-transplant in the PBMCs.

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