title: Proof-of-Principle for Immune Control of Global HIV-1 Reactivation In Vivo.
abstract: BACKGROUND
  Emerging data relating to human immunodeficiency virus type 1 (HIV-1) cure suggest that vaccination to stimulate the host immune response, particularly cytotoxic cells, may be critical to clearing of reactivated HIV-1-infected cells. However, evidence for this approach in humans is lacking, and parameters required for a vaccine are unknown because opportunities to study HIV-1 reactivation are rare.
  
  
  METHODS
  We present observations from a HIV-1 elite controller, not treated with combination antiretroviral therapy, who experienced viral reactivation following treatment for myeloma with melphalan and autologous stem cell transplantation. Mathematical modeling was performed using a standard viral dynamic model. Enzyme-linked immunospot, intracellular cytokine staining, and tetramer staining were performed on peripheral blood mononuclear cells; in vitro CD8 T-cell-mediated control of virion production by autologous CD4 T cells was quantified; and neutralizing antibody titers were measured.
  
  
  RESULTS
  Viral rebound was measured at 28,000 copies/mL on day 13 post-transplant before rapid decay to <50 copies/mL in 2 distinct phases with t1/2 of 0.71 days and 4.1 days. These kinetics were consistent with an expansion of cytotoxic effector cells and killing of productively infected CD4 T cells. Following transplantation, innate immune cells, including natural killer cells, recovered with virus rebound. However, most striking was the expansion of highly functional HIV-1-specific cytotoxic CD8 T cells, at numbers consistent with those applied in modeling, as virus control was regained.
  
  
  CONCLUSIONS
  These observations provide evidence that the human immune response is capable of controlling coordinated global HIV-1 reactivation, remarkably with potency equivalent to combination antiretroviral therapy. These data will inform design of vaccines for use in HIV-1 curative interventions.
authors.affiliation: Nuffield Department of Medicine, University of Oxford.
authors.forename: Nicola M G
authors.initials: NM
authors.lastname: Smith
authors.affiliation: Department of Infection, Division of Infection and Immunity, University College London.
authors.forename: Petra
authors.initials: P
authors.lastname: Mlcochova
authors.affiliation: Department of Infection, Division of Infection and Immunity, University College London.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Watters
authors.affiliation: Department of Infection, Division of Infection and Immunity, University College London.
authors.forename: Marlene M I
authors.initials: MM
authors.lastname: Aasa-Chapman
authors.affiliation: University College London Hospitals National Health Service (NHS) Foundation Trust.
authors.forename: Neil
authors.initials: N
authors.lastname: Rabin
authors.affiliation: University College London Hospitals National Health Service (NHS) Foundation Trust.
authors.forename: Sally
authors.initials: S
authors.lastname: Moore
authors.affiliation: Mortimer Market Centre, Central and North West London NHS Foundation Trust, United Kingdom.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Edwards
authors.affiliation: Department of Infection, Division of Infection and Immunity, University College London.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Garson
authors.affiliation: University College London Hospitals National Health Service (NHS) Foundation Trust.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Grant
authors.affiliation: Department of Infection, Division of Infection and Immunity, University College London.
authors.forename: R Bridget
authors.initials: RB
authors.lastname: Ferns
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill.
authors.forename: Angela
authors.initials: A
authors.lastname: Kashuba
authors.affiliation: Anthony Nolan Research Institute, Royal Free Hospital Cancer Institute, University College London, United Kingdom.
authors.forename: Neema P
authors.initials: NP
authors.lastname: Mayor
authors.affiliation: Anthony Nolan Research Institute, Royal Free Hospital Cancer Institute, University College London, United Kingdom.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schellekens
authors.affiliation: Anthony Nolan Research Institute, Royal Free Hospital Cancer Institute, University College London, United Kingdom.
authors.forename: Steven G E
authors.initials: SG
authors.lastname: Marsh
authors.affiliation: Nuffield Department of Medicine, University of Oxford.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
authors.affiliation: Los Alamos National Laboratory, New Mexico.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
authors.affiliation: Department of Infection, Division of Infection and Immunity, University College London Africa Centre for Health and Population Sciences, University of KwaZulu Natal, South Africa.
authors.forename: Deenan
authors.initials: D
authors.lastname: Pillay
authors.affiliation: Nuffield Department of Medicine, University of Oxford Department of Microbiology & Immunology, University of North Carolina at Chapel Hill.
authors.forename: Nilu
authors.initials: N
authors.lastname: Goonetilleke
authors.affiliation: Department of Infection, Division of Infection and Immunity, University College London.
authors.forename: Ravindra K
authors.initials: RK
authors.lastname: Gupta
mesh_terms: D057134:Antibodies, Neutralizing / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000032:analysis; D058501:Enzyme-Linked Immunospot Assay; D015483:HIV Antibodies / Q000097:blood; D015658:HIV Infections / Q000150:complications / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D008558:Melphalan / Q000009:adverse effects / Q000627:therapeutic use; D008875:Middle Aged; D008962:Models, Theoretical; D009101:Multiple Myeloma / Q000188:drug therapy; D019653:Myeloablative Agonists / Q000009:adverse effects / Q000627:therapeutic use; D033581:Stem Cell Transplantation / Q000009:adverse effects; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014182:Transplantation, Autologous; D014775:Virus Activation / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D016207:Cytokines; D015483:HIV Antibodies; D019653:Myeloablative Agonists; D008558:Melphalan
keywords: CD8; HIV; cure; elite control; myeloablation