Mechanistic regulation of HERV activation in tumors and implications for translational research in oncology.

Transcription of distinct loci of human endogenous retroviruses (HERVs) and in some cases, translation of these transcripts have been consistently observed in many types of cancer. It is still debated whether HERV activation serves as a trigger for carcinogenesis or rather occurs as a consequence of epigenetic alterations and other molecular sequelae that characterize cellular transformation. Here we review the known molecular and epigenetic mechanisms of HERV activation in cancer cells as well as its potential contribution to carcinogenesis. Further, we describe the use of HERV expression in cancer diagnostic and characterize the potential of HERV-derived antigens to serve as novel targets for cancer immunotherapy. We believe this review, which summarizes both what is known as well as unknown in this rapidly developing field, will boost interest in research on the therapeutic potential of targeting HERV elements in tumors and the impact of HERV activation in oncogenesis.

Antigenic evolution of vaccine-derived polioviruses: changes in individual epitopes and relative stability of the overall immunological properties.

The Sabin oral poliovirus vaccine (OPV) readily undergoes changes in antigenic sites upon replication in humans. Here, a set of antigenically altered descendants of the three OPV serotypes (76 isolates) was characterized to determine the driving forces behind these changes and their biological implications. The amino acid residues of OPV derivatives that lie within or close to the known antigenic sites exhibited a marked tendency to be replaced by residues characteristic of homotypic wild polioviruses, and these changes may occur very early in OPV evolution. The specific amino acid alterations nicely correlated with serotype-specific changes in the reactivity of certain individual antigenic sites, as revealed by the recently devised monoclonal antibody-based enzyme-linked immunosorbent assay. In comparison to the original vaccine, small changes, if any, in the neutralizing capacity of human or rabbit sera were observed in highly diverged vaccine polioviruses of three serotypes, in spite of strong alterations of certain epitopes. We propose that the common antigenic alterations in evolving OPV strains largely reflect attempts to eliminate fitness-decreasing mutations acquired either during the original selection of the vaccine or already present in the parental strains. Variability of individual epitopes does not appear to be primarily caused by, or lead to, a significant immune evasion, enhancing only slightly, if at all, the capacity of OPV derivatives to overcome immunity in human populations. This study reveals some important patterns of poliovirus evolution and has obvious implications for the rational design of live viral vaccines.

Retrospective analysis of a local cessation of vaccination against poliomyelitis: a possible scenario for the future.

The global eradication of poliomyelitis will require substantial changes in immunization practices. One of the proposed scenarios includes cessation of vaccination with live oral poliovirus vaccine (OPV) and the creation of an OPV stockpile for emergency response in case of the reintroduction of poliovirus into circulation. We describe here a retrospective analysis of the cessation of OPV usage in a region of the Byelorussian Republic of the former Soviet Union in 1963 to 1966. During this period, a widespread circulation and evolution of independent lineages of vaccine-derived polioviruses took place in the region. Some of these lineages appeared to originate from OPV given to 40 children in the community during this period of essentially no vaccinations. The data demonstrate very high risks associated with both the local cessation of OPV vaccination and the proposed use of OPV to control a possible reemergence of poliovirus in the postvaccination period. The high transmissibility of OPV-derived viruses in nonimmune population, documented here, and the known existence of long-term OPV excretors should be also considered in assessing risks of the synchronized global cessation of OPV usage.

Long-term circulation of vaccine-derived poliovirus that causes paralytic disease.

Successful implementation of the global poliomyelitis eradication program raises the problem of vaccination against poliomyelitis in the posteradication era. One of the options under consideration envisions completely stopping worldwide the use of the Sabin vaccine. This strategy is based on the assumption that the natural circulation of attenuated strains and their derivatives is strictly limited. Here, we report the characterization of a highly evolved derivative of the Sabin vaccine strain isolated in a case of paralytic poliomyelitis from a 7-month-old immunocompetent baby in an apparently adequately immunized population. Analysis of the genome of this isolate showed that it is a double (type 1-type 2-type 1) vaccine-derived recombinant. The number of mutations accumulated in both the type 1-derived and type 2-derived portions of the recombinant genome suggests that both had diverged from their vaccine predecessors approximately 2 years before the onset of the illness. This fact, along with other recent observations, points to the possibility of long-term circulation of Sabin vaccine strain derivatives associated with an increase in their neurovirulence. Comparison of genomic sequences of this and other evolved vaccine-derived isolates reveals some general features of natural poliovirus evolution. They include a very high preponderance and nonrandom distribution of synonymous substitutions, conservation of secondary structures of important cis-acting elements of the genome, and an apparently adaptive character of most of the amino acid mutations, with only a few of them occurring in the antigenic determinants. Another interesting feature is a frequent occurrence of tripartite intertypic recombinants with either type 1 or type 3 homotypic genomic ends.