title: Multiple Origins of Virus Persistence during Natural Control of HIV Infection.
abstract: Targeted HIV cure strategies require definition of the mechanisms that maintain the virus. Here, we tracked HIV replication and the persistence of infected CD4 T cells in individuals with natural virologic control by sequencing viruses, T cell receptor genes, HIV integration sites, and cellular transcriptomes. Our results revealed three mechanisms of HIV persistence operating within distinct anatomic and functional compartments. In lymph node, we detected viruses with genetic and transcriptional attributes of active replication in both T follicular helper (TFH) cells and non-TFH memory cells. In blood, we detected inducible proviruses of archival origin among highly differentiated, clonally expanded cells. Linking the lymph node and blood was a small population of circulating cells harboring inducible proviruses of recent origin. Thus, HIV replication in lymphoid tissue, clonal expansion of infected cells, and recirculation of recently infected cells act together to maintain the virus in HIV controllers despite effective antiviral immunity.
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Eli A
authors.initials: EA
authors.lastname: Boritz
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Darko
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Luke
authors.initials: L
authors.lastname: Swaszek
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Gideon
authors.initials: G
authors.lastname: Wolf
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: David
authors.initials: D
authors.lastname: Wells
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Henry
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Farida
authors.initials: F
authors.lastname: Laboune
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Hu
authors.affiliation: Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ambrozak
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, NCI, NIH, Bethesda, MD 20892, USA.
authors.forename: Marybeth S
authors.initials: MS
authors.lastname: Hughes
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hoh
authors.affiliation: Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Casazza
authors.affiliation: Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Vostal
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bunis
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Krystelle
authors.initials: K
authors.lastname: Nganou-Makamdop
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Migueles
authors.affiliation: Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
authors.affiliation: Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
authors.affiliation: Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Moir
authors.affiliation: Program in HIV Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Schacker
authors.affiliation: HIV Dynamics and Replication Program, NCI, NIH, Frederick, MD 21702, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Maldarelli
authors.affiliation: HIV Dynamics and Replication Program, NCI, NIH, Frederick, MD 21702, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA. Electronic address: ddouek@mail.nih.gov.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
mesh_terms: D001769:Blood / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D004279:DNA, Viral / Q000235:genetics; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear; D008198:Lymph Nodes / Q000821:virology; D011533:Proviruses / Q000276:immunology; D017422:Sequence Analysis, DNA; D018406:Virus Physiological Phenomena; D014779:Virus Replication
chemical_list: D004279:DNA, Viral