Abstract
Human endogenous retrovirus (HERV) genomes are chromosomally integrated in all cells of an individual. They are normally transcriptionally silenced and transmitted only vertically. Enhanced expression of HERV-K accompanied by the emergence of anti-HERV-K-directed immune responses has been observed in tumor patients and HIV-infected individuals. As HERV-K is usually not expressed and immunological tolerance development is unlikely, it is an appropriate target for the development of immunotherapies. We generated a recombinant vaccinia virus (MVA-HKenv) expressing the HERV-K envelope glycoprotein (ENV), based on the modified vaccinia virus Ankara (MVA), and established an animal model to test its vaccination efficacy. Murine renal carcinoma cells (Renca) were genetically altered to express E. coli beta-galactosidase (RLZ cells) or the HERV-K ENV gene (RLZ-HKenv cells). Intravenous injection of RLZ-HKenv cells into syngenic BALB/c mice led to the formation of pulmonary metastases, which were detectable by X-gal staining. A single vaccination of tumor-bearing mice with MVA-HKenv drastically reduced the number of pulmonary RLZ-HKenv tumor nodules compared to vaccination with wild-type MVA. Prophylactic vaccination of mice with MVA-HKenv precluded the formation of RLZ-HKenv tumor nodules, whereas wild-type MVA-vaccinated animals succumbed to metastasis. Protection from tumor formation correlated with enhanced HERV-K ENV-specific killing activity of splenocytes. These data demonstrate for the first time that HERV-K ENV is a useful target for vaccine development and might offer new treatment opportunities for diverse types of cancer.
Highlights
Human endogenous retroviruses (HERVs) are relics of evolutionary ancient viral infection events into the germ line which are transmitted vertically
Like all retroviral envelope proteins, the HERV-K envelope glycoprotein (ENV) is translated as a precursor protein from a singly spliced transcript
Two vaccinations on days 0 and 21 of BALB/c mice with 107 IU modified vaccinia virus Ankara (MVA)-HKenv resulted in the weak generation of ENV-specific antibodies by the mice, as analyzed on day 47 by immunofluorescence studies with GH cells, which express high levels of HERV-K ENV protein and are a very sensitive method to detect
Summary
Human endogenous retroviruses (HERVs) are relics of evolutionary ancient viral infection events into the germ line which are transmitted vertically. These retrovirus genomes are chromosomally integrated in all the cells of an individual and their sequences comprise about 8% of the human genome [1]. HERVs are classified by the single letter amino acid code for the tRNA specific for the primer-binding site used to initiate reverse transcription. 11 distantly related HERV groups with a tRNA lysine (K) primer binding site are known (reviewed in [2]). The HERV-K/HML-2(hom) group, is the only known endogenous retrovirus group encoding all structural and enzymatic proteins. HERV-K/HML2(hom) will hereafter be abridged to HERV-K
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