title: Short Intracellular HIV-1 Transcripts as Biomarkers of Residual Immune Activation in Patients on Antiretroviral Therapy.
abstract: HIV-1 patients continue to remain at an abnormal immune status despite prolonged combination antiretroviral therapy (cART), which results in an increased risk of non-AIDS-related diseases. Given the growing recognition of the importance of understanding and controlling the residual virus in patients, additional virological markers to monitor infected cells are required. However, viral replication in circulating cells is much poorer than that in lymph nodes, which results in the absence of markers to distinguish these cells from uninfected cells in the blood. In this study, we identified prematurely terminated short HIV-1 transcripts (STs) in peripheral blood mononuclear cells (PBMCs) as an efficient intracellular biomarker to monitor viral activation and immune status in patients with cART-mediated full viral suppression in plasma. STs were detected in PBMCs obtained from both treated and untreated patients. ST levels in untreated patients generally increased with disease progression and decreased after treatment initiation. However, some patients exhibited sustained high levels of ST and low CD4(+) cell counts despite full viral suppression by treatment. The levels of STs strongly reflected chronic immune activation defined by coexpression of HLA-DR and CD38 on CD8(+) T cells, rather than circulating proviral load. These observations represent evidence for a relationship between viral persistence and host immune activation, which in turn results in the suboptimal increase in CD4(+) cells despite suppressive antiretroviral therapy. This cell-based measurement of viral persistence contributes to an improved understanding of the dynamics of viral persistence in cART patients and will guide therapeutic approaches targeting viral reservoirs.
  
  
  
  Combination antiretroviral therapy (cART) suppresses HIV-1 load to below the detectable limit in plasma. However, the virus persists, and patients remain at an abnormal immune status, which results in an increased risk of non-AIDS-related complications. To achieve a functional cure for HIV-1 infection, activities of viral reservoirs must be quantified and monitored. However, latently infected cells are difficult to be monitored. Here, we identified prematurely terminated short HIV-1 transcripts (STs) as an efficient biomarker for monitoring viral activation and immune status in patients with cART-mediated full viral suppression in plasma. This cell-based measurement of viral persistence will contribute to our understanding of the impact of residual virus on chronic immune activation in HIV-1 patients during cART.
authors.affiliation: Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Tokyo, Microbial Chemistry Research Foundation, Shinagawa-ku, Tokyo, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Ishizaka
authors.affiliation: Division of Infectious Disease, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Sato
authors.affiliation: Division of Infectious Disease, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.|Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Division of Infectious Disease, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Koga
authors.affiliation: Division of Infectious Disease, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: Division of Infectious Disease, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.|Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Hosoya
authors.affiliation: Department of Infectious Diseases and Applied Immunology, IMSUT Hospital, the Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Koibuchi
authors.affiliation: Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Tokyo, Microbial Chemistry Research Foundation, Shinagawa-ku, Tokyo, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Nomoto
authors.affiliation: Division of Infectious Disease, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.|AIDS Research Center, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Kawana-Tachikawa
authors.affiliation: Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Tokyo, Microbial Chemistry Research Foundation, Shinagawa-ku, Tokyo, Japan mizutanit@bikaken.or.jp.
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Mizutani
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D015415:Biomarkers / Q000097:blood; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000821:virology; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D011533:Proviruses / Q000235:genetics / Q000302:isolation & purification; D012367:RNA, Viral / Q000097:blood / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D019562:Viral Load
chemical_list: D015415:Biomarkers; D006684:HLA-DR Antigens; D008562:Membrane Glycoproteins; D012367:RNA, Viral; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1