Importance of the Intracytoplasmic Domain of the Simian Immunodeficiency Virus (SIV) Envelope Glycoprotein for Pathogenesis

AbstractSIVmac1A11 and SIVmac239 are nonpathogenic and pathogenic molecular clones in rhesus macaques, respectively. Although these viruses exhibit ∼98% nucleotide and amino acid sequence homology, differences are found in the length of the translation frames for several genes. SIVmac239 has a premature stop codon innef, whereas SIVmac1A11 has a premature stop codon invprand two premature stop codons in the intracytoplasmic domain of theenv-transmembrane (TM) subunit. Recombinant viruses, constructed through reciprocal exchange of large DNA restriction enzyme fragments between SIVmac1A11 and SIVmac239, were evaluated in adult rhesus macaques. Thisin vivoanalysis revealed that two or more regions of the SIVmac genome were essential for high virus load and disease progression (Marthaset al.,1993.J. Virol.67, 6047–6055). An important gap in knowledge remaining from this study was whether the premature stop codons inenv-TM of recombinant virus SIV1A11/239gag-env/1A11 (full-lengthvprandnef, two stop codons inenv-TM) reverted to coding tripletsin vivo. Here, we report that viral sequences in macaques, which succumbed to an AIDS-like disease after infection with SIV1A11/239gag-env/1A11, exhibited reversion of bothenv-TM stop codons. In addition, antibodies to the intracytoplasmic domain ofenv-TM were detected in macaques containing revertant virus and showing disease; this finding indicates that this domain of theenvglycoprotein was expressedin vivo. Thus selection for viral variants with full-lengthenv-TM demonstrated that the cytoplasmic domain of the SIVmacenvglycoprotein plays a role in viral persistence and immunodeficiency in primates