Hijacking the T-cell communication network by the human T-cell leukemia/lymphoma virus type 1 (HTLV-1) p12 and p8 proteins

The non-structural proteins encoded by the orf-I, II, III, and IV genes of the human T-cell leukemia/lymphoma virus type 1 (HTLV-1) genome, are critical for the modulation of cellular gene expression and T-cell proliferation, the escape from cytotoxic T-cells and natural killer cells, and virus expression. In here, we review the main functions of the HTLV-1 orf-I products. The 12 kDa product from orf-I (p12) is proteolytically cleaved within the endoplasmic reticulum (ER) to generate the 8 kDa protein (p8). At the steady state, both proteins are expressed at similar levels in transfected T-cells. The p12 protein remains in the ER and cis-Golgi, whereas the p8 protein traffics to the cell surface and is recruited to the immunological synapse. The p12 and the p8 proteins have seemingly opposite effects on T-cells; the ER resident p12, modulates T-cell activation and proliferation, whereas p8 induces T-cell anergy. The p8 protein also increases the formation of cellular conduits, is transferred to neighboring T-cells, and increases virus transmission. The requirement for HTLV-1 infectivity of orf-I is demonstrated by the loss of virus infectivity in macaques exposed to an engineered virus, whereby expression of orf-I was ablated. Altogether the current knowledge demonstrates that the concerted activity of p8 and p12 is essential for the persistence of virus infected cells in the host.