HTLV-1 Yin and Yang: Rex and p30 master regulators of viral mRNA trafficking

Human retroviruses are associated with a variety of malignancies including Kaposi's sarcoma and Epstein-Barr virus-associated lymphoma in HIV infection, T-cell leukemia/lymphoma and a neurologic disorder in human T-cell lymphotropic virus type 1 (HTLV-1) infection. Both HIV and human T-cell lymphotropic virus type 1 have evolved a complex genetic organization for optimal use of their limited genome and production of all necessary structural and regulatory proteins. Use of alternative splicing is essential for balanced expression of multiple viral regulators from one genomic polycistronic RNA. In addition, nuclear export of incompletely spliced RNA is required for production of structural and enzymatic proteins and virus particles. Decisions controlling these events are largely guarded by viral proteins. In human T-cell lymphotropic virus type 1, Rex and p30 are both nuclear/nucleolar RNA binding regulatory proteins. Rex interacts with a Rex-responsive element to stimulate nuclear export of incompletely spliced RNA and increase production of virus particles. In contrast, human T-cell lymphotropic virus type 1 p30 is involved in the nuclear retention of the tax/rex mRNA leading to inhibition of virus expression and establishment of viral latency. How these two proteins, with apparently opposite functions, orchestrate virus replication and ensure vigilant control of viral gene expression is discussed.