PROLONGED INFECTION IN RHESUS MACAQUES WITH SIMIAN IMMUNODEFICIENCY VIRUS (SIV(MAC)239) RESULTS IN ANIMAL-SPECIFIC AND RARELY TISSUE-SPECIFIC SELECTION OF NEF VARIANTS

We analyzed the sequence of nef genes from different tissues of three rhesus macaques that had been infected with molecularly cloned SIV(mac )239 for 88 to 92 weeks. Comparison of the predicted amino acid sequen ces revealed that each macaque had selected out specific amino acid su bstitutions and that most of this variation (70%) was confined to four regions, amino acids 39 to 75, 90 to 105, 153 to 167, and 191 to 217, comprising 36% of the protein. The nef genes in these animals underwe nt extensive genetic variation with average nucleotide and amino acid substitution rates varying from 0.86 to 2.84% and 2.47 to 6.27%, respe ctively, although tissue-specific selection of nef variants occurred i n only 1 of 14 tissues examined in this study. Comparison of the rate of nucleotide and amino acid substitutions in the nef genes to those p reviously reported in the env in the central nervous system (CNS) and lymph node (LN) revealed that the predicted amino acid substitution ra tes for Nef were much higher than for the gp120 region of env in the C NS and LN tissues for one macaque. In the two other macaques, the pred icted amino acid substitution rates were similar between these two pro teins in LN tissues, but the amino acid substitution rates in Nef were significantly higher than in the gp120 from the CNS. Comparison of th e nucleotide substitutions in the region of overlap between the env an d the nef revealed that approximately 83% of the nucleotide substituti ons in this area resulted in a Nef amino acid sequence change, 26% of the nucleotide substitutions resulted in a gp41 amino acid change, and 9.5% of nucleotide substitutions resulted in amino acid sequence chan ges in both proteins, suggesting a preference for the selection of ami no acid substitutions in the Nef in these animals. Our results indicat e that in animals infected with SIV(mac)239 for prolonged periods, var iation in the nef occurs at rates similar to or exceeding that observe d for the env gene. (C) 1996 Academic Press, Inc.