title: Live, attenuated simian immunodeficiency virus SIVmac-M4, with point mutations in the Env transmembrane protein intracytoplasmic domain, provides partial protection from mucosal challenge with pathogenic SIVmac251.
abstract: Attenuated molecular clones of simian immunodeficiency virus (SIVmac) are important tools for studying the correlates of protective immunity to lentivirus infection in nonhuman primates. The most highly attenuated SIVmac mutants fail to induce disease but also fail to induce immune responses capable of protecting macaques from challenge with pathogenic virus. We recently described a novel attenuated virus, SIVmac-M4, containing multiple mutations in the transmembrane protein (TM) intracytoplasmic domain. This domain has been implicated in viral assembly, infectivity, and cytopathogenicity. Whereas parental SIVmac239-Nef(+) induced persistent viremia and simian AIDS in rhesus macaques, SIVmac-M4 induced transient viremia in juvenile and neonatal macaques, with no disease for at least 1 year postinfection. In this vaccine study, 8 macaques that were infected as juveniles (n = 4) or neonates (n = 4) with SIVmac-M4 were challenged with pathogenic SIVmac251 administered through oral mucosa. At 1 year postchallenge, six of the eight macaques had low to undetectable plasma viremia levels. Assays of cell-mediated immune responses to SIVmac Gag, Pol, Env, and Nef revealed that all animals developed strong CD8(+) T-cell responses to Gag after challenge but not before. Unvaccinated control animals challenged with SIVmac251 developed persistent viremia, had significantly weaker SIV-specific T-cell responses, and developed AIDS-related symptoms. These findings demonstrate that SIVmac-M4, which contains a full-length Nef coding region and multiple point mutations in the TM, can provide substantial protection from mucosal challenge with pathogenic SIVmac251.
authors.affiliation: Gladstone Institute of Virology and Immunology, University of California-San Francisco, San Francisco 94141-9100, USA. bshacklett@gladstone.ucsf.edu
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Shacklett
authors.forename: Karen E S
authors.initials: KE
authors.lastname: Shaw
authors.forename: Lou A
authors.initials: LA
authors.lastname: Adamson
authors.forename: David T
authors.initials: DT
authors.lastname: Wilkens
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Cox
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: Murray B
authors.initials: MB
authors.lastname: Gardner
authors.forename: Pierre
authors.initials: P
authors.lastname: Sonigo
authors.forename: Paul A
authors.initials: PA
authors.lastname: Luciw
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000914:Antibodies, Viral; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015686:Gene Products, env / Q000235:genetics / Q000276:immunology*; D008253:Macaca mulatta; D009061:Mouth Mucosa / Q000821:virology; D009500:Neutralization Tests; D017354:Point Mutation; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000276:immunology*; D018449:SAIDS Vaccines / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000276:immunology; D014760:Viral Fusion Proteins / Q000235:genetics / Q000276:immunology*; D019562:Viral Load
chemical_list: D000914:Antibodies, Viral; D015686:Gene Products, env; D015682:Retroviridae Proteins, Oncogenic; D018449:SAIDS Vaccines; D014613:Vaccines, Attenuated; D014760:Viral Fusion Proteins; C059580:transmembrane protein, Simian immunodeficiency virus