Combined Cytolytic Effects of a Vaccinia Virus Encoding a Single Chain Trimer of MHC-I with a Tax-Epitope and Tax-Specific CTLs on HTLV-I-Infected Cells in a Rat Model

Abstract

Adult T cell leukemia (ATL) is a malignant lymphoproliferative disease caused by human T cell leukemia virus type I (HTLV-I). To develop an effective therapy against the disease, we have examined the oncolytic ability of an attenuated vaccinia virus (VV), LC16m8Δ (m8Δ), and an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) line, 4O1/C8, against an HTLV-I-infected rat T cell line, FPM1. Our results demonstrated that m8Δ was able to replicate in and lyse tumorigenic FPM1 cells but was incompetent to injure 4O1/C8 cells, suggesting the preferential cytolytic activity toward tumor cells. To further enhance the cytolysis of HTLV-I-infected cells, we modified m8Δ and obtained m8Δ/RT1AlSCTax180L, which can express a single chain trimer (SCT) of rat major histocompatibility complex class I with a Tax-epitope. Combined treatment with m8Δ/RT1AlSCTax180L and 4O1/C8 increased the cytolysis of FPM1V.EFGFP/8R cells, a CTL-resistant subclone of FPM1, compared with that using 4O1/C8 and m8Δ presenting an unrelated peptide, suggesting that the activation of 4O1/C8 by m8Δ/RT1AlSCTax180L further enhanced the killing of the tumorigenic HTLV-I-infected cells. Our results indicate that combined therapy of oncolytic VVs with SCTs and HTLV-I-specific CTLs may be effective for eradication of HTLV-I-infected cells, which evade from CTL lysis and potentially develop ATL.

Human T-cell lymphotropic virus type 1 (HTLV-1) proposed vaccines: a systematic review of preclinical and clinical studies

“…Previous studies supported the use of this technique to develop vaccines against influenza virus [ 79 ], parainfluenza virus [ 80 ], and human immunodeficiency virus type 1 (HIV-l) [ 81 ]. Regarding HTLV-1, our search identified 8 studies which used vaccinia virus to develop HTLV-1 vaacine [ 34 , 36 , 43 , 45 , 52 , 68 , 69 , 71 , 82 ]. Except three [ 52 , 71 , 82 ], all studies were conducted before 2000 [ 34 , 36 , 43 , 45 , 68 , 69 ].…”

“…Regarding HTLV-1, our search identified 8 studies which used vaccinia virus to develop HTLV-1 vaacine [ 34 , 36 , 43 , 45 , 52 , 68 , 69 , 71 , 82 ]. Except three [ 52 , 71 , 82 ], all studies were conducted before 2000 [ 34 , 36 , 43 , 45 , 68 , 69 ]. One of the studies were an in-vitro study performed by Arp et al [ 34 ] and was aimed to express HTLV-1 gp46 envelope protein in a vaccinia virus.…”

Advances in preventive vaccine development against HTLV-1 infection: A systematic review of the last 35 years

“…Some of these seek to develop a safe and viable treatment option for ATLL. The promising results were: a pilot study that evaluated the response of patients to a Tax peptide (Tax-DC) pulsed dendritic cell vaccine; and a proposed vaccine expressed from the vaccinia virus, which presents an oncolytic activity that can be an effective tool in the eradication of tumors ( 77 , 78 ). In this sense, Sugata K et al., 2015 also proposed a therapeutic vaccination for ATLL treatment using infected monkeys.…”

HTLV-1 Infection and Pathogenesis: New Insights from Cellular and Animal Models

“…Transgenic CRMI1 rats intraperitoneally inoculated with HTLV-1-infected cells exhibited a much higher HTLV-1 viral production than wild type rats, and presented more extensive invasion of the thymus by HTLV-1, supporting the in vitro evidence of the key role of CRM1 in HTLV-1 infection [ 133 ]. Rat models were also used to test the effect of vaccines based on HTLV-1 Tax-specific cytotoxic T lymphocyte immunity response, the oncolytic potential of vaccinia viruses (VVs) and the ability of siRNA Tax downregulated HTLV-1-infected cells to develop tumors in T-cell-deficient nude rats [ 134 , 135 , 136 ]. These studies confirm the significant roles of Tax in activating cytotoxic host immune response to the virus and in the survival of infected cells in vivo.…”