Vaccination against Endogenous Retrotransposable Element Consensus Sequences Does Not Protect Rhesus Macaques from SIVsmE660 Infection and Replication

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.

Identification and spontaneous immune targeting of an endogenous retrovirus K envelope protein in the Indian rhesus macaque model of human disease

“…Thus, the LL15- and PA8-specific T cell responses in r02120 likely represent genuine targeting of SERV-K1 Env and not cross-reactive SIV-specific T cell responses. This is in line with a previous report indicating lack of SIV-induced up-regulation of SERV activity in the cells of rhesus macaques [ 21 ]. Thus, viral infection status alone does not predict SERV-K1-specific T cell immunity.…”

“…ELISPOT screening was carried out as previous described [ 26 ] using 15-mer peptides (with 11 amino acid overlap) spanning the entire SERV-K1 Env open reading frame or the entire SIVmac239 proteome. Intracellular cytokine staining assays were carried out as previously described [ 21 , 26 ]. Positive responses shown were confirmed using peptides synthesized by three independent sources.…”

The decline of human endogenous retroviruses: extinction and survival

“…In contrast, the small env -containing family, HK2, may have continued to replicate exclusively in humans. The apparent extinction of the sister lineage of HK2 in the macaque is significant as this lineage is being investigated as a model for testing a possible ERV-based immunotherapy for HIV in humans [ 20 , 30 , 31 ]. The extinction explains why other studies have reported finding only a few full-length ORFs in this family [ 20 , 30 ].…”

Nonhuman primate models for the evaluation of HIV-1 preventive vaccine strategies

“…While SIVmac239 and SIVmac251 have a degree of resistance to antibody-mediated neutralization comparable to or exceeding typical circulating HIV-1 strains [52–54**], the SIVsmE660 isolate is composed of viral clones most of which are relatively more neutralization sensitive [48], making it a more tractable target for antibody-based prevention studies. However, unlike the SIVmac viruses, SIVsmE660 and E543 are highly susceptible to restriction by specific rhesus macaque TRIM5α alleles [55–58], which can impact virus acquisition after mucosal challenge [57,58], confounding the interpretation of vaccine efficacy [59,60]. Thus, when using SIVsmE660 and related challenge viruses, it is critical to genotype study animals for their TRIM5α alleles and either exclude those with restrictive TRIM5α alleles or account for the distribution of restrictive and permissive alleles among the study arms.…”