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Replication-dependent fitness recovery of Human immunodeficiency virus 1 harbouring mutations of Asn17 of the nucleocapsid protein

József Tözsér^1,2,

Sergey Shulenin^1,,

¹ National Cancer Institute, Frederick, MD 21701, USA
² Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, Debrecen University, H-4012 Debrecen, Hungary

Correspondence
Stephen Oroszlan
oroszlans{at}mail.ncifcrf.gov

The genetic stability of attenuated Human immunodeficiency virus 1 (HIV-1) variants harbouring mutations (Gly or Lys) of Asn17, the protease-cleavage site of the proximal zinc finger of the nucleocapsid protein, was studied. All possible codons for the Gly mutants were tested as starting sequences. Long-term replication assays revealed that the mutants were unstable; mutations of Gly17 to Arg, Ala, Ser and Cys, as well as a Lys17Asn reversion, were observed. Replication kinetic assays in H9 cells revealed that the replication of Ala, Ser and Arg mutants was improved substantially compared with the Gly variant; the infectivity of Ala17 and Ser17 viruses was equal to, and that of Arg17 was almost equal to, the infectivity of the wild-type virus. Kinetic analysis of the cleavage of oligopeptides representing the corresponding nucleocapsid-cleavage sites revealed that all mutations improved cleavability, in good agreement with the previously proposed role of nucleocapsid cleavage in HIV-1 replication.

These authors contributed equally to this paper.

Present address: A&G Pharmaceutical, Suite U, 9130 Red Branch Road, Columbia, MD 21045, USA.