title: The intracytoplasmic domain of the Env transmembrane protein is a locus for attenuation of simian immunodeficiency virus SIVmac in rhesus macaques.
abstract: The human and simian immunodeficiency virus (HIV-1 and SIVmac) transmembrane proteins contain unusually long intracytoplasmic domains (ICD-TM). These domains are suggested to play a role in envelope fusogenicity, interaction with the viral matrix protein during assembly, viral infectivity, binding of intracellular calmodulin, disruption of membranes, and induction of apoptosis. Here we describe a novel mutant virus, SIVmac-M4, containing multiple mutations in the coding region for the ICD-TM of pathogenic molecular clone SIVmac239. Parental SIVmac239-Nef+ produces high-level persistent viremia and simian AIDS in both juvenile and newborn rhesus macaques. The ICD-TM region of SIVmac-M4 contains three stop codons, a +1 frameshift, and mutation of three highly conserved, charged residues in the conserved C-terminal alpha-helix referred to as lentivirus lytic peptide 1 (LLP-1). Overlapping reading frames for tat, rev, and nef are not affected by these changes. In this study, four juvenile macaques received SIVmac-M4 by intravenous injection. Plasma viremia, as measured by branched-DNA (bDNA) assay, reached a peak at 2 weeks postinoculation but dropped to below detectable levels by 12 weeks. At over 1.5 years postinoculation, all four juvenile macaques remain healthy and asymptomatic. In a subsequent experiment, four neonatal rhesus macaques were given SIVmac-M4 intravenously. These animals exhibited high levels of viremia in the acute phase (2 weeks postinoculation) but are showing a relatively low viral load in the chronic phase of infection, with no clinical signs of disease for 1 year. These findings demonstrated that the intracytoplasmic domain of the transmembrane Env (Env-TM) is a locus for attenuation in rhesus macaques.
authors.affiliation: Aaron Diamond AIDS Research Center, New York, NY, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Shacklett
authors.forename: C J
authors.initials: CJ
authors.lastname: Weber
authors.forename: K E
authors.initials: KE
authors.lastname: Shaw
authors.forename: E M
authors.initials: EM
authors.lastname: Keddie
authors.forename: M B
authors.initials: MB
authors.lastname: Gardner
authors.forename: P
authors.initials: P
authors.lastname: Sonigo
authors.forename: P A
authors.initials: PA
authors.lastname: Luciw
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D019556:COS Cells; D015686:Gene Products, env / Q000235:genetics* / Q000276:immunology; D015693:Gene Products, nef / Q000235:genetics / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008253:Macaca mulatta; D017434:Protein Structure, Tertiary / Q000235:genetics; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics* / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D014760:Viral Fusion Proteins / Q000235:genetics* / Q000276:immunology; D014779:Virus Replication
chemical_list: D000914:Antibodies, Viral; D015686:Gene Products, env; D015693:Gene Products, nef; D015682:Retroviridae Proteins, Oncogenic; D014760:Viral Fusion Proteins; C059580:transmembrane protein, Simian immunodeficiency virus