Human T-lymphotropic virus type 1 (HTLV-1) is classified as a complex retrovirus and a member of the genus Deltaretrovirus. The HTLV-1 genome consists of long terminal repeats; genes encoding the structural and enzymatic proteins Gag, Pol, and Env; and a pX region located between env and the 3Ј long terminal repeat that encodes the regulatory proteins Tax and Rex, as well as several nonstructural "accessory" proteins, p12 II (12,16,28,30). HTLV-1 is the etiological agent of adult T-cell leukemia/lymphoma (ATL), a highly aggressive T-cell malignancy (reviewed in reference 43). The virus is also associated with lymphocyte-mediated inflammatory diseases, such HTLV-1-associated myelopathy-tropical spastic paraparesis (16,24,27). There are an estimated 15 to 25 million persons persistently infected by HTLV-1, and approximately 3 to 5% of these infected subjects will develop HTLV-1-associated diseases (27). The underlying mechanisms by which HTLV-1 establishes a persistent infection and transforms lymphocytes has been extensively investigated but incompletely understood. Based on the long period of latency and the low percentage of individuals who develop ATL, transformation of infected lymphocytes is believed to be initiated through the induction of cellular genes and alterations in cellular activation and death pathways by HTLV-1 proteins (18,35).Recent studies indicate a significant role for HTLV-1 accessory proteins in the life cycle of HTLV-1, particularly during the early phase of the viral infection of lymphocytes (reviewed in references 12, 28, and 32). Less is known about the accessory protein p13II , a singly spliced product of the second open reading frame (ORF II) of the pX gene region. p13II mRNA is expressed in various HTLV-1-infected cell lines isolated from clinical patients of ATL and HTLV-1-associated myelopathytropical spastic paraparesis (5, 36), and circulating cytotoxic lymphocytes specific to ORF II products (i.e., p13 II and p30 II ) have been detected both in HTLV-1-infected ATL patients and in asymptomatic persons (34). p13 II localizes and accumulates in the inner membranes of mitochondria, and when ectopically expressed, it causes alteration of mitochondrial morphology and function (7,12). We recently reported the suppressive effect of p13 II on both cell growth in vitro and tumorigenicity in a murine model (12,38) and the sensitization of lymphocytes to apoptosis in a Ras-dependent fashion (19). Collectively, these observations indicate a distinct role for p13 II in HTLV-1 infection and a potential role in HTLV-1-mediated lymphocyte transformation. Although initial studies reported that HTLV-1 ORF II was dispensable for viral infection in vitro (15, 37), disruption of pX ORF II in an HTLV-1 proviral clone that blocks expression of full-length p30 II alone or both p30 II and p13 II dramatically reduced viral infectivity and host humoral response in rabbits (2, 39). These studies, * Corresponding author. Mailing address: Department of Veterinary Biosciences, The Ohio State University, 1925 C...