Vaccination with Cancer- and HIV Infection-Associated Endogenous Retrotransposable Elements Is Safe and Immunogenic

Abstract

The expression of endogenous retrotransposable elements including Long Interspersed Nuclear Element-1 (LINE-1 or L1) and Human Endogenous Retrovirus (HERV)-K accompanies neoplastic transformation and infection with viruses such as HIV. The ability to engender immunity safely against such self-antigens would facilitate the development of novel vaccines and immunotherapies. Here we address the safety and immunogenicity of vaccination with these elements. We employed immunohistochemical analysis and literature-precedent to identify potential off-target tissues in humans and establish their translatability in preclinical species to guide safety assessments. Immunization of mice with murine L1 Open Reading Frame-2 (L1O2) induced strong CD8 T cell responses without detectable tissue damage. Similarly, immunization of rhesus macaques with human L1O2 (96% identity with macaque), and Simian ERV (SERV)-K Gag and Env induced polyfunctional T cell responses to all antigens, and antibody responses to SERV-K Env. There were no adverse safety or pathology findings related to vaccination. These studies provide the first evidence that immune responses can be induced safely against this class of self antigens, and pave the way for their investigation as HIV- or tumor-associated targets.

HERV-K–specific T cells eliminate diverse HIV-1/2 and SIV primary isolates

“…The etiology of these unusual features is unclear but may be related to clonal deletion of higher-avidity HERV-K(HML-2)-specific T cells. In this regard, it is interesting to note that when we have vaccinated mice against murine L1 retrotransposable element antigens, we have observed that robust T cell responses were detectable upon screening with overlapping 9-mer peptides, while, in parallel, a complete lack of responses was observed with overlapping 15-mer peptides (30). Comprehensive evaluation of HERV-K(HML-2)-specific T cell responses may therefore require the application of more sensitive methods, such as DC-mediated expansions.…”

“…In moving toward developing this vaccine strategy, it is important to consider whether immune tolerance to HERV-K(HML-2) antigens is likely to exist and, if so, whether breaking such tolerance may carry the risk of inducing autoimmunity. While HERV-K(HML-2) RNA appears to be readily detected in all tissues, including the thymus (33), we are of the position that the expression of HERV-K(HML-2)-Gag and -Env protein has not been convincingly demonstrated in any healthy adult human tissue, despite extensive screening (30). The fact that we are not able to more readily detect T cell responses to these antigens in HIV-1-infected individuals using 15-mers may be indicative of tolerance (29).…”

Cutting Edge: An Antibody Recognizing Ancestral Endogenous Virus Glycoproteins Mediates Antibody-Dependent Cellular Cytotoxicity on HIV-1–Infected Cells

“…The safety and immunogenicity of such a vaccine were already demonstrated in nonhuman primates (15). Modulating HERV-K-specific humoral immunity may represent a novel approach in the quest to prevent and eradicate HIV-1 infection.…”

Does HERV-K represent a potential therapeutic target for prostate cancer?

“…This issue is crucial if Gag is to be used as a target for immunotherapies. Notably, vaccines against endogenous retroviruses are generally considered safe [17], although any specific vaccine will require individual testing for adverse effects, especially unintended autoimmunity. For their application, two scenarios may be envisioned.…”