Viral domains contributing to SIV replication in brain.

Important note: Information in this article was accurate in 1994. The state of the art may have changed since the publication date.

Viral domains contributing to SIV replication in brain.

Symp Nonhum Primate Models AIDS. 1993 Sep 19-22;11:abstract no. 32. Unique Identifier : AIDSLINE PRIM11/94191626
Kodama T; Kawahara T; Desrosiers R; Axthelm M; Oregon Regional Primate Research Center, Beaverton 97006.

Abstract: We have isolated SIVmac155/NT variants from the brain of a rhesus macaque that displayed encephalitis after infection with cloned SIVmac239. Compared to parental SIVmac239, the NT variant exhibited high replicative capacity for peripheral macrophages and primary brain cell cultures from rhesus macaques, but it replicated very poorly in human T-cell lines and PHA-stimulated rhesus lymphocytes. Specific genetic changes were identified in the gp120 of the NT variant. To examine the role of gp120 sequences in the properties of the NT variant, gp120 sequences derived from the NT variant were subcloned into SIVmac239 to generate Ev/N1 env recombinant virus. Unlike parental SIVmac239, Ev/N1 was able to replicate in both rhesus peripheral blood macrophages and brain cells, indicating that gp120 of the NT variant is one of the genetic determinants for replication in brain. However, replication of the Ev/N1 recombinant in macrophage and brain cell cultures was relatively low compared to that of the uncloned NT variant. Furthermore, in contrast to the NT variant, the Ev/N1 recombinant replicated significantly in human T-cell lines and rhesus lymphocytes. We next investigated whether viral domains other than gp120 may contribute to the properties of the NT variant. Viral DNA spanning from gp41 to the 3'LTR region of the NT variant was recombined into the Ev/N1 env recombinant to generate a recombinant called N1/neu3'. N1/neu3' contains gp120, gp41, nef and 3'LTR of the NT variant. N1/neu3' showed a pattern of replication strikingly similar to the NT variant in cultures; N1/neu3' showed enhanced ability to replicate in brain cell cultures compared to Ev/N1, but replicated very poorly in human T-cell lines and rhesus lymphocytes. We also recombined the region from gp41 to the 3'LTR of NT into SIVmac239 to generate recombinant 239/neu3'. The gp41 to 3'LTR fragment derived from NT significantly reduced the ability of SIVmac239 to replicate in human T-cell lines and PHA-stimulated lymphocytes, but did not confer the ability to replicate in macrophages and brain cells. A total of 10 amino acid changes were observed in the gp41 of the NT variant, two of them located at the N-terminus of gp41, a region involved in membrane fusion. A total of 7 amino acid changes were observed in the nef coding region and 4 nucleotide changes were observed in the 3'LTR. These data demonstrate that gp120 is a major genetic determinant of the replicative capacity of the NT variant for brain cells and indicate that gp41 to the 3'LTR region of NT contains viral domains to enhance this ability and alter the replicative capacity for lymphocytes as well.

Keywords: Animal Brain/*MICROBIOLOGY Cells, Cultured Comparative Study Genes, env Genes, nef Human HIV Envelope Protein gp120/GENETICS Lymphocyte Transformation Macaca mulatta Macrophages/MICROBIOLOGY Recombination, Genetic Repetitive Sequences, Nucleic Acid Simian Acquired Immunodeficiency Syndrome/*MICROBIOLOGY SIV/*GENETICS/ISOLATION & PURIF/*PHYSIOLOGY T-Lymphocytes/IMMUNOLOGY/MICROBIOLOGY *Virus Replication ABSTRACT
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M9470892

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