title: Human T-cell leukemia virus type 2 antisense viral protein 2 is dispensable for in vitro immortalization but functions to repress early virus replication in vivo.
abstract: Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 are closely related but pathogenically distinct human retroviruses. The antisense strand of the HTLV-1 genome encodes HTLV-1 basic leucine zipper (b-ZIP) protein (HBZ), a protein that inhibits Tax-mediated viral transcription, enhances T-cell proliferation, and promotes viral persistence. Recently, an HTLV-2 antisense viral protein (APH-2) was identified. Despite its lack of a typical b-ZIP domain, APH-2, like HBZ, interacts with cyclic AMP response element binding protein (CREB) and downregulates Tax-mediated viral transcription. Here, we provide evidence that the APH-2 C-terminal LXXLL motif is important for CREB binding and Tax repression. In order to investigate the functional role of APH-2 in the HTLV-2-mediated immortalization of primary T lymphocytes in vitro and in HTLV-2 infection in vivo, we generated APH-2 mutant viruses. In cell cultures, the immortalization capacities of APH-2 mutant viruses were indistinguishable from that of wild-type HTLV-2 (wtHTLV-2), indicating that, like HBZ, APH-2 is dispensable for viral infection and cellular transformation. In vivo, rabbits inoculated with either wtHTLV-2 or APH-2 mutant viruses established a persistent infection. However, the APH-2 knockout virus displayed an increased replication rate, as measured by an increased viral antibody response and a higher proviral load. In contrast to HTLV-1 HBZ, we show that APH-2 is dispensable for the establishment of an efficient infection and persistence in a rabbit animal model. Therefore, antisense proteins of HTLV-1 and HTLV-2 have evolved different functions in vivo, and further comparative studies will provide fundamental insights into the distinct pathobiologies of these two viruses.
authors.affiliation: Center for Retrovirus Research, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Yin
authors.forename: Priya
authors.initials: P
authors.lastname: Kannian
authors.forename: Nathan
authors.initials: N
authors.lastname: Dissinger
authors.forename: Robyn
authors.initials: R
authors.lastname: Haines
authors.forename: Stefan
authors.initials: S
authors.lastname: Niewiesk
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Green
mesh_terms: D000818:Animals; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D016356:Gene Products, tax / Q000378:metabolism; D015491:HTLV-II Infections / Q000821:virology; D015367:Human T-lymphotropic virus 2 / Q000502:physiology*; D006801:Humans; D011485:Protein Binding; D011817:Rabbits; D013601:T-Lymphocytes / Q000821:virology; D014764:Viral Proteins / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D016356:Gene Products, tax; D014764:Viral Proteins; C514971:tax protein, Human T-lymphotrophic virus 2