Determinants of increased replicative capacity of serially passaged simian immunodeficiency virus with nef deleted in rhesus monkeys

Louis Alexander, Petr O. Illyinskii, Sabine M. Lang, Robert E. Means, Jeffrey Lifson, Keith Mansfield, Ronald C. Desrosiers

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

Most rhesus macaques infected with simian immunodeficiency virus SIVmac239 with nef deleted (either Anef or ΔnefΔvprΔUS [Δ3]) control viral replication and do not progress to AIDS. Some monkeys, however, develop moderate viral load set points and progress to AIDS. When simian immunodeficiency viruses (SIVs) recovered from two such animals (one Δnef and the other Δ3) were serially passaged in rhesus monkeys, the SIVs derived from both lineages were found to consistently induce moderate viral loads and disease progression. Analysis of viral sequences in the serially passaged derivatives revealed interesting changes in three regions: (i) an unusually high number of predicted amino acid changes (12 to 14) in the cytoplasmic domain of gp41, most of which were in regions that are usually conserved; these changes were observed in both lineages; (ii) an extreme shortening of nef sequences in the region of overlap with U3; these changes were observed in both lineages; and (iii) duplication of the NF-κB binding site in one lineage only. Neither the polymorphic gp41 changes alone nor the U3 deletion alone appeared to be responsible for increased replicative capacity because recombinant SIVmac239Δnef, engineered to contain either of these changes, induced moderate viral loads in only one of six monkeys. However, five of six monkeys infected with recombinant SIVmac239Δnef containing both TM and U3 changes did develop persisting moderate viral loads. These genetic changes did not increase lymphoid cell activating properties in the monkey interleukin-2-dependent T-cell line 221, but the gp41 changes did increase the fusogenic activity of the SIV envelope two- to threefold. These results delineate sequence changes in SIV that can compensate for the loss of the nef gene to partially restore replicative and pathogenic potential in rhesus monkeys.

Original languageEnglish (US)
Pages (from-to)6823-6835
Number of pages13
JournalJournal of virology
Volume77
Issue number12
DOIs
StatePublished - Jun 2003

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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