Functional Conservation of HTLV-1 Rex Balances the Immune Pressure for Sequence Variation in theRexGene

Abstract

Naturally occurring mutations in Human T-cell Leukemia Virus Type 1 (HTLV-1) Tax protein lead to loss of recognition by cytotoxic T-lymphocytes. Most of these mutations also abolish or severely impair the transactivation function of Tax. Ninety percent of therexgene, which encodes the viral regulator of mRNA splicing (Rex), overlaps with thetaxgene. In this paper, we report that four previously described point mutations intaxthat abolished CTL recognition and activity did not alter either the dimerisation function or the ability to export viral mRNA of the corresponding Rex proteins. Rex proteins containing two other amino acid changes were likewise functional. However, five Rex deletion mutants, predominantly but not exclusively found in HAM/TSP patients, had all lost these functions. We conclude that, although the Tax protein is subject to strong CTL-mediated selection, there are stronger functional constraints on amino acid variation in Rex. This may limit the variation in thetax/rexnucleotide sequence which results in immune evasion.