title: Lack of viral control and development of combination antiretroviral therapy escape mutations in macaques after bone marrow transplantation.
abstract: OBJECTIVE
  We have previously demonstrated robust control of simian/human immunodeficiency virus (SHIV1157-ipd3N4) viremia following administration of combination antiretroviral therapy (cART) in pigtailed macaques. Here, we sought to determine the safety of hematopoietic stem cell transplantation (HSCT) in cART-suppressed and unsuppressed animals.
  
  
  METHODS
  We compared disease progression in animals challenged with SHIV 100 days post-transplant, to controls that underwent transplant following SHIV challenge and stable cART-dependent viral suppression.
  
  
  METHODS
  SHIV viral load, cART levels, and anti-SHIV antibodies were measured longitudinally from plasma/serum from each animal. Flow cytometry was used to assess T-cell subset frequencies in peripheral blood and the gastrointestinal tract. Deep sequencing was used to identify cART resistance mutations.
  
  
  RESULTS
  In control animals, virus challenge induced transient peak viremia, viral set point, and durable suppression by cART. Subsequent HSCT was not associated with adverse events in these animals. Post-transplant animals were challenged during acute recovery following HSCT, and displayed sustained peak viremia and cART resistance. Although post-transplant animals had comparable plasma levels of antiretroviral drugs and showed no evidence of enhanced infection of myeloid subsets in the periphery, they exhibited a drastic reduction in virus-specific antibody production and decreased T-cell counts.
  
  
  CONCLUSIONS
  These results suggest that virus challenge prior to complete transplant recovery impairs viral control and may promote drug resistance. These findings may also have implications for scheduled treatment interruption studies in patients on cART during post-HSCT recovery: premature scheduled treatment interruption could similarly result in lack of viral control and cART resistance.
authors.affiliation: aClinical Research Division, Fred Hutchinson Cancer Research Center bWashington National Primate Research Center, Seattle cVaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington dDivision of Pharmacotherapy and Experimental Therapeutics, University of North Carolina, Chapel Hill, North Carolina eDepartment of Microbiology fDepartment of Pediatrics gDepartment of Laboratory Medicine hDepartment of Medicine iDepartment of Pharmaceutics jDepartment of Pathology, University of Washington, Seattle, Washington, USA. *Christopher W. Peterson and Kevin G. Haworth contributed equally to the writing of this article.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Peterson
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Haworth
authors.forename: Patricia
authors.initials: P
authors.lastname: Polacino
authors.forename: Meei-Li
authors.initials: ML
authors.lastname: Huang
authors.forename: Craig
authors.initials: C
authors.lastname: Sykes
authors.forename: Willimark M
authors.initials: WM
authors.lastname: Obenza
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Repetto
authors.forename: Angela
authors.initials: A
authors.lastname: Kashuba
authors.forename: Roger
authors.initials: R
authors.lastname: Bumgarner
authors.forename: Stephen C
authors.initials: SC
authors.lastname: DeRosa
authors.forename: Ann E
authors.initials: AE
authors.lastname: Woolfrey
authors.forename: Keith R
authors.initials: KR
authors.lastname: Jerome
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.forename: Shiu-Lok
authors.initials: SL
authors.lastname: Hu
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Kiem
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D000914:Antibodies, Viral / Q000097:blood; D018450:Disease Progression; D024882:Drug Resistance, Viral; D005434:Flow Cytometry; D041981:Gastrointestinal Tract / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D059014:High-Throughput Nucleotide Sequencing; D008137:Longitudinal Studies; D008251:Macaca; D008297:Male; D020125:Mutation, Missense; D010949:Plasma / Q000737:chemistry / Q000821:virology; D012367:RNA, Viral / Q000235:genetics; D016097:Simian Acquired Immunodeficiency Syndrome / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D019562:Viral Load
chemical_list: D044966:Anti-Retroviral Agents; D000914:Antibodies, Viral; D012367:RNA, Viral