Human T-cell leukemia virus type 1 (HTLV-1) establishes a persistent infection in the host despite a vigorous virus-specific immune response. Here we demonstrate that an HTLV-1-encoded protein, p12I, resides in the endoplasmic reticulum (ER) and Golgi and physically binds to the free human major histocompatibility complex class I heavy chains (MHC-I-Hc) encoded by the HLA-A2,-B7, and-Cw4 alleles. As a result of this interaction, the newly synthesized MHC-I-Hc fails to associate with ß2-microglobulin and is retrotranslocated to the cytosol, where it is degraded by the proteasome complex. Targeting of the free MHC-I-Hc, and not the MHC-I-Hc–ß2-microglobulin complex, by p12I represents a novel mechanism of viral interference and disrupts the intracellular trafficking of MHC-I, which results in a significant decrease in surface levels of MHC-I on human T-cells. These findings suggest that the interaction of p12I with MHC-1-Hc may interfere with antigen presentation in vivo and facilitate escape of HTLV-1-infected cells from immune recognition.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATLL)(16, 55, 37), as well as the neurologic disorder tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP-HAM)(14, 33, 42). HTLV-1 induces a lifelong chronic infection, which may result in ATLL in 1 to 5% of carriers 20 to 30 years after infection. Despite a vigorous host immune response, HTLV-1 persists in the infected host, suggesting that the virus may have developed strategies to evade the host’s immune response, as is the case with other chronic viruses (36, 49). The major histocompatibility complex class I (MHC-I) molecules, which are essential for presentation of foreign peptides to the host cytotoxic T lymphocytes (CTL), are targets of many pathogens, including viruses (36, 49). CTL recognize virusinfected cells through the specific interaction of their T-cell receptor with an MHC-I molecule presenting a viral peptide. The MHC-I complex consists of a heavy chain (Hc) containing the peptide binding site and 2-microglobulin, which assemble very rapidly in the lumen of the endoplasmic reticulum (ER). Peptides, generated by the proteasome in the cytoplasm, are translocated by TAP (transporter associated with antigen processing) into the ER where they assemble in ternary complexes and are transported to the cell surface for presentation to CTL (54). Interference with the assembly and/or trafficking of the MHC-I complex can contribute to the persistence of a virus,