Expression of Human Endogenous Retrovirus Type K (HML-2) Is Activated by the Tat Protein of HIV-1

Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Journal of Virology (Impact Factor: 4.44). 05/2012; 86(15):7790-805. DOI: 10.1128/JVI.07215-11
Source: PubMed


Human endogenous retroviruses (HERVs) make up 8% of the human genome. The expression of HERV-K (HML-2), the family of HERVs
that most recently entered the genome, is tightly regulated but becomes markedly increased after infection with HIV-1. To
better understand the mechanisms involved in this activation, we explored the role of the HIV-1 Tat protein in inducing the
expression of these endogenous retroviral genes. Administration of recombinant HIV-1 Tat protein caused a 13-fold increase
in HERV-K (HML-2) gag RNA transcripts in Jurkat T cells and a 10-fold increase in primary lymphocytes, and the expression of the HERV-K (HML-2)
rec and np9 oncogenes was also markedly increased. This activation was seen especially in lymphocytes and monocytic cells, the natural
hosts for HIV-1 infection. Luciferase reporter gene assays demonstrated that the effect of Tat on HERV-K (HML-2) expression
occurred at the level of the transcriptional promoter. The transcription factors NF-κB and NF-AT contribute to the Tat-induced
activation of the promoter, as shown by chromatin immunoprecipitation assays, mutational analysis of the HERV-K (HML-2) long
terminal repeat, and treatments with agents that inhibit NF-κB or NF-AT activation. These studies demonstrate that HIV-1 Tat
plays an important role in activating expression of HERV-K (HML-2) in the setting of HIV-1 infection.

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    • "For gene expression analyses of np9 and gag genes, we used the KAPA SYBR FAST qPCR Kit Master Mix (2 Â ) Universal (Kapa Biosystems) and a Corbett Rotor-Gene 6000. HERVs-K primer sequences of np9 and gag were previously described [2] [8]. The cellular c-myc expression level in CLL patients was also assessed with respect to healthy donors. "
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    ABSTRACT: The human genome contains a large number of endogenous retroviruses (HERVs). Their reactivation has frequently been observed in patients with cancer. Considering their role in the carcinogenesis process, we aimed to study the possible relationship between HERVs gene expression and Chronic Lymphocytic Leukemia (CLL). We focused on two viral genes: gag and np9, the latter presumably an oncogene. We found that the transcriptional activity of HERV-K np9 gene was greater in CLL patients than in healthy donors. However, gag expression was not significantly increased. These findings suggest a noteworthy relationship between CLL disease and HERV-K np9 expression.
    Leukemia Research Reports 07/2014; 3(2). DOI:10.1016/j.lrr.2014.06.005
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    • "A direct link between HERV-K activation and HIV infection was suggested recently [24]. Gonzalez-Hernandez and colleagues reported that addition of recombinant HIV-1 Tat protein to Jurkat cells caused a 13-fold increase in HERV-K gag RNA transcripts and a 10-fold increase in treated primary lymphocytes [24]. "
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    ABSTRACT: Human endogenous retroviruses (HERVs) are remnants of ancestral infections and chromosomally integrated in all cells of an individual, are transmitted only vertically and are defective in viral replication. However enhanced expression of HERV-K accompanied by the emergence of anti-HERV-K-directed immune responses has been observed inter-alia in HIV-infected individuals and tumor patients. Therefore HERV-K might serve as a tumor-specific antigen or even as a constant target for the development of an HIV vaccine. To verify our hypothesis, we tested the immunogenicity of HERV-K Gag by using a recombinant vaccinia virus (MVA-HKcon) expressing the HERV-K Gag protein and established an animal model to test its vaccination efficacy. Murine renal carcinoma cells (Renca) were genetically altered to express E. coli beta-galactosidase (RLZ cells) and the HERV-K Gag protein (RLZ-HKGag cells). Subcutaneous application of RLZ-HKGag cells into syngenic BALB/c mice resulted in the formation of local tumors in MVA vaccinated mice. MVA-HKcon vaccination reduced the tumor growth. Furthermore, intravenous injection of RLZ-HKGag cells led to the formation of pulmonary metastases. Vaccination of tumor-bearing mice with MVA-HKcon drastically reduced the number of pulmonary RLZ-HKGag tumor nodules compared to vaccination with wild-type MVA. The data demonstrate that HERV-K Gag is a useful target for vaccine development and might offer new treatment opportunities for cancer patients. .
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    • "Based on the inability of our vaccine-induced, ERE-specific T cells to recognize SIV-infected cells we next investigated whether SIV induced expression of these antigens at the mRNA level in rhesus macaque cells, as we and others have previously observed with HERV-K transcripts in HIV-1-infected human cells [10]. To this end, we infected activated CD4+ T cells with SIVsmE660 via magnetofection and used the highly SIV-infected populations at 72 and 96 for qPCR analysis (Fig. 5A). "
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    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.
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