T Cell Responses to Human Endogenous Retroviruses in HIV-1 Infection

Abstract

Human endogenous retroviruses (HERVs) are remnants of ancient infectious agents that have integrated into the human genome. Under normal circumstances, HERVs are functionally defective or controlled by host factors. In HIV-1-infected individuals, intracellular defense mechanisms are compromised. We hypothesized that HIV-1 infection would remove or alter controls on HERV activity. Expression of HERV could potentially stimulate a T cell response to HERV antigens, and in regions of HIV-1/HERV similarity, these T cells could be cross-reactive. We determined that the levels of HERV production in HIV-1-positive individuals exceed those of HIV-1-negative controls. To investigate the impact of HERV activity on specific immunity, we examined T cell responses to HERV peptides in 29 HIV-1-positive and 13 HIV-1-negative study participants. We report T cell responses to peptides derived from regions of HERV detected by ELISPOT analysis in the HIV-1-positive study participants. We show an inverse correlation between anti-HERV T cell responses and HIV-1 plasma viral load. In HIV-1-positive individuals, we demonstrate that HERV-specific T cells are capable of killing cells presenting their cognate peptide. These data indicate that HIV-1 infection leads to HERV expression and stimulation of a HERV-specific CD8+ T cell response. HERV-specific CD8+ T cells have characteristics consistent with an important role in the response to HIV-1 infection: a phenotype similar to that of T cells responding to an effectively controlled virus (cytomegalovirus), an inverse correlation with HIV-1 plasma viral load, and the ability to lyse cells presenting their target peptide. These characteristics suggest that elicitation of anti-HERV-specific immune responses is a novel approach to immunotherapeutic vaccination. As endogenous retroviral sequences are fixed in the human genome, they provide a stable target, and HERV-specific T cells could recognize a cell infected by any HIV-1 viral variant. HERV-specific immunity is an important new avenue for investigation in HIV-1 pathogenesis and vaccine design.

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

“…Early support for the induction of HERV antigen expression in HIV-1-infected subjects was provided by our observation that T cell responses to a variety of HERV-derived peptides are detectable in HIV-1-infected subjects but not in uninfected controls (25,26). Supporting the in vivo relevance of these responses, we observed that strong HERV-specific T cell responses were associated with control of HIV-1 replication (25,27). However, these observations could have resulted from a number of etiologies and are insufficient to either infer HIV-1-induced HERV expression or to validate HERV antigens as novel HIV-1 vaccine targets.…”

“…We have previously presented the hypothesis that the manipulation of the host cellular environment by HIV-1 to one which favors retroviral expression and replication may result in the expression of HERV proteins (25). Following from this, we have speculated that such expression could be targeted by HERV-specific T cells, resulting in the specific elimination of HIV-1-infected cells.…”

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

“…We showed previously that HERV mRNA transcripts and protein are present in the cells of HIV-1-infected patients and that HERV-K (HML-2)-specific T cells can eliminate HIV-1-infected cells in vitro (6,11). In this study, we used a human Ab (HA-137), which recognizes the HIV-1-induced HERV-K (HML-2) TM protein (7), to test for ADCC activity on HIV-1-infected cells.…”

“…HERV-K (HML-2), the most recently integrated HERV, was reported to express proteins in some disease states (4,5). During HIV-1 infection, HERV-K mRNA transcripts and viral proteins can be detected in serum (6,7). The mechanisms of interaction between HIV-1 and HERV-K are still under investigation, but the HIV-1 accessory proteins Vif and Tat are thought to play a role in HERV-K protein expression (8,9).…”

Tumorigenesis related to retroviral infections

“…They derive from the integration of exogenous, infectiously transmitted retroviruses in the host genomes and are followed by genetic stabilization through accumulation of mutations [4,10]. Under normal circumstances, HERVs are functionally defective or controlled by host factors [9][10][11]. Several types of HERVs belong to the betaretroviruses and gammaretroviruses genera [4].…”