title: Sequential CCR5-Tropic HIV-1 Reactivation from Distinct Cellular Reservoirs following Perturbation of Elite Control.
abstract: BACKGROUND
  HIV Elite Controllers may reveal insights into virus persistence given they harbour small reservoir sizes, akin to HIV non-controllers treated early with combination antiretroviral therapy. Both groups of patients represent the most promising candidates for interventions aimed at sustained remission or 'cure'. Analytic treatment interruption (ATI) in the latter group leads to stochastic rebound of virus, though it is unclear whether loss of elite control is also associated with similar rebound characteristics.
  
  
  METHODS
  We studied three discrete periods of virus rebound during myeloma related immune disruption over 2.5 years in an elite controller who previously underwent autologous stem cell transplantation (ASCT) in the absence of any antiretroviral therapy. Single genome sequencing of the V1-V4 region of env in PBMC and plasma was performed and phylogenies reconstructed. Average pairwise distance (APD) was calculated and non-parametric methods used to assess compartmentalisation. Coreceptor usage was predicted based on genotypic algorithms.
  
  
  RESULTS
  122 single genome sequences were obtained (median 26 sequences per rebound). The initial rebounding plasma env sequences following ASCT represented two distinct lineages, and clustered with proviral DNA sequences isolated prior to ASCT. One of the lineages was monophyletic, possibly indicating reactivation from clonally expanded cells. The second rebound occurred 470 days after spontaneous control of the first rebound and was phylogenetically distinct from the first, confirmed by compartmentalisation analysis, with a different cellular origin rather than ongoing replication. By contrast, third rebound viruses clustered with second rebound viruses, with evidence for ongoing evolution that was associated with lymphopenia and myeloma progression. Following ASCT a shift in tropism from CXCR4-tropic viruses to a CCR5-tropic population was observed to persist through to the third rebound.
  
  
  CONCLUSIONS
  Our data highlight similarities in the viral reservoir between elite and non-controllers undergoing ATI following allogeneic transplantation. The lack of propagation of CXCR4 using viruses following transplantation warrants further study.
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.|HIV Dynamics and Replication Program, NCI, Frederick, Maryland, United States of America.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Watters
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Petra
authors.initials: P
authors.lastname: Mlcochova
authors.affiliation: HIV Dynamics and Replication Program, NCI, Frederick, Maryland, United States of America.
authors.forename: Frank
authors.initials: F
authors.lastname: Maldarelli
authors.affiliation: Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Nilu
authors.initials: N
authors.lastname: Goonetilleke
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.|Africa Centre for Health and Population Studies, Durban, KwaZulu-Natal, South Africa.
authors.forename: Deenan
authors.initials: D
authors.lastname: Pillay
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Ravindra K
authors.initials: RK
authors.lastname: Gupta
mesh_terms: D055011:Ablation Techniques / Q000009:adverse effects; D001853:Bone Marrow / Q000601:surgery; D015497:HIV-1 / Q000502:physiology*; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology / Q000601:surgery / Q000821:virology; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D012008:Recurrence; D033581:Stem Cell Transplantation; D013269:Stochastic Processes; D056189:Viral Tropism; D014775:Virus Activation
chemical_list: D019713:Receptors, CCR5; D019718:Receptors, CXCR4