Role of Human T-cell Leukemia Virus Type I (HTLV-I) Regulatory Proteins in Viral Replication

Abstract

The pX region at the 3’ end of the HTLV-1 genome encodes alternatively spliced mRNAs for nonstructural proteins such as HBZ, p12/8, and p30. In vitro studies have demonstrated that ectopic expression of these proteins results in decreased viral replication: HBZ directly antagonizes Tax transcriptional activity by competing with CREB/ATF; p30 decreases viral replication by a post transcriptional mechanism and retains the Tax/Rex mRNA in the nucleus. p12 modulates T-cell proliferation and downregulates the major histocompatibility class I heavy chain complex expression. p8 affects viral replication indirectly by dampening TCR signaling. In the present study, we generated mutants that selectively ablate expression of p12/8, p30, and HBZ (Δp12, Δp8, Δp30, ΔHBZ). We inoculated a total of 30 rabbits (5 rabbits per group). Control animals were inoculated with lethally irradiated 729 uninfected human B cell line. The remaining groups received ~1x108 lethally irradiated cells harboring wild-type (WT) or Δp12, Δp8, Δp30, ΔHBZ Within four weeks all animals inoculated with the wt or mutant viruses seroconverted, and all where either positive by virus isolation from PBMC or by PCR for proviral DNA. Quantitative assessment of virus load in blood of all animals revealed between 1 log decrease for Δp30 and Δp12 and 2 logs decrease for animals infected with the ΔHBZ virus. Interestingly, the Δp8 mutant, produced a proviral load which was higher than that in animals infected with the WT virus.