Abstract
The enormous sequence diversity of HIV remains a major roadblock to the development of a prophylactic vaccine and new approaches to induce protective immunity are needed. Endogenous retrotransposable elements (ERE) such as endogenous retrovirus K (ERV)-K and long interspersed nuclear element-1 (LINE-1) are activated during HIV-1-infection and could represent stable, surrogate targets to eliminate HIV-1-infected cells. Here, we explored the hypothesis that vaccination against ERE would protect macaques from acquisition and replication of simian immunodeficiency virus (SIV). Following vaccination with antigens derived from LINE-1 and ERV-K consensus sequences, animals mounted immune responses that failed to delay acquisition of SIVsmE660. We observed no differences in acute or set point viral loads between ERE-vaccinated and control animals suggesting that ERE-specific responses were not protective. Indeed, ERE-specific T cells failed to expand anamnestically in vivo following infection with SIVsmE660 and did not recognize SIV-infected targets in vitro, in agreement with no significant induction of targeted ERE mRNA by SIV in macaque CD4+ T cells. Instead, lower infection rates and viral loads correlated significantly to protective TRIM5α alleles. Cumulatively, these data demonstrate that vaccination against the selected ERE consensus sequences in macaques did not lead to immune-mediated recognition and killing of SIV-infected cells, as has been shown for HIV-infected human cells using patient-derived HERV-K-specific T cells. Thus, further research is required to identify the specific nonhuman primate EREs and retroviruses that recapitulate the activity of HIV-1 in human cells. These results also highlight the complexity in translating observations of the interplay between HIV-1 and human EREs to animal models.
Highlights
HIV vaccine research has yielded numerous novel strategies
Contradictory reports exist on the relationship between human endogenous retrovirus (HERV)-K activation and HIV replication [55,56], we, and others, have found selected antigens to be associated with HIV infection [2,3,4,5,6,7,8]
Repressive mechanisms targeting endogenous retrotransposable elements (ERE) act at many levels both pre- and post-transcription [14] [15] [22] [24], and it is not clear how HIV/simian immunodeficiency virus (SIV) triggers ERE expression, changes in mRNA levels might not relate to changes in Simian ERV (SERV)-K and L1 translation
Summary
HIV vaccine research has yielded numerous novel strategies. These approaches have yet to effectively address the enormous amount of HIV sequence diversity present within and between infected hosts. Others, have observed that certain ERE including specific human endogenous retrovirus (HERV) families [2,3,4,5,6,7,8,9,10,11] and long interspersed nuclear element (LINE)-1 insertions [12], which normally remain dormant in healthy somatic cells, are activated following HIV infection. Inducing similar immune responses directed to HERV-K, and LINE-1, by vaccination represents a novel HIV vaccine strategy, but one that faces complex hurdles regarding safety and immunogenicity due to the potential for recognition of self-antigens
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