Selective Ablation of Human T-Cell Lymphotropic Virus Type 1 p12I Reduces Viral Infectivity In Vivo

Abstract

Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia and HTLV-1-associated myelopathy. Novel, yet conserved RNA transcripts encoded from open reading frames (ORFs) I and II of the viral pX region are expressed both in vitro and in infected individuals. The ORF I mRNA encodes the protein p12^I, which has been shown to localize to cellular endomembranes, cooperate with bovine papillomavirus E5 in transformation, as well as bind to the IL-2 receptor β and γ chains and the H⁺ vacuolar ATPase. It is unknown what role p12^I plays in the viral life cycle. Using an infectious molecular clone of HTLV-1 (ACH) and a derivative clone, ACH.p12^I, which fails to produce the p12^Imessage, we investigated the importance of p12^I in infected primary cells and in a rabbit model of the infection. ACH.p12^I was infectious in vitro as shown by viral passage in culture and no qualitative or quantitative differences were noted between ACH and ACH.p12^I in posttransfection viral antigen production. However, in contrast to ACH, ACH.p12^I failed to establish persistent infection in vivo as indicated by reduced anti-HTLV-1 antibody responses, failure to demonstrate viral p19 antigen production in peripheral blood mononuclear cell (PBMC) cultures, and only transient detection of provirus by polymerase chain reaction in PBMC from ACH.p12^I-inoculated rabbits. These results are the first to show the essential role of HTLV-1 p12^I in the establishment of persistent viral infection in vivo and suggest potential new targets in antiviral strategies to prevent HTLV-1 infection.