HIV-1 infection activates endogenous retroviral promoters regulating antiviral gene expression

Abstract

Although endogenous retroviruses (ERVs) are known to harbor cis-regulatory elements, their role in modulating cellular immune responses remains poorly understood. Using an RNA-seq approach, we show that several members of the ERV9 lineage, particularly LTR12C elements, are activated upon HIV-1 infection of primary CD4+ T cells. Intriguingly, HIV-1-induced ERVs harboring transcription start sites are primarily found in the vicinity of immunity genes. For example, HIV-1 infection activates LTR12C elements upstream of the interferon-inducible genes GBP2 and GBP5 that encode for broad-spectrum antiviral factors. Reporter assays demonstrated that these LTR12C elements drive gene expression in primary CD4+ T cells. In line with this, HIV-1 infection triggered the expression of a unique GBP2 transcript variant by activating a cryptic transcription start site within LTR12C. Furthermore, stimulation with HIV-1-induced cytokines increased GBP2 and GBP5 expression in human cells, but not in macaque cells that naturally lack the GBP5 gene and the LTR12C element upstream of GBP2. Finally, our findings suggest that GBP2 and GBP5 have already been active against ancient viral pathogens as they suppress the maturation of the extinct retrovirus HERV-K (HML-2). In summary, our findings uncover how human cells can exploit remnants of once-infectious retroviruses to regulate antiviral gene expression.

When human guanylate-binding proteins meet viral infections

“…Notably, GBP2 and GBP5 targeted only highly pathogenic avian influenza viruses harboring a furin cleavage site in their hemagglutinin [ 46 , 47 ]. A recent study also showed that GBP2 and GBP5 suppressed furin-mediated maturation of the envelope protein of human endogenous retrovirus K [ 48 ] (Fig. 1 b).…”

Switching Sides: How Endogenous Retroviruses Protect Us from Viral Infections

“…These two GTPases exert broad antiviral activity by inhibiting the virus-dependency factor furin (109). Intriguingly, numerous LTR12C and related LTR12D elements are activated upon HIV-1 infection (107,110), suggesting that they may be part of a larger network regulating antiviral immune responses. In line with this, expression of an LTR12C-SEMA4D fusion transcript is also increased in HIV-1 infected cells (107).…”

“…Intriguingly, numerous LTR12C and related LTR12D elements are activated upon HIV-1 infection (107,110), suggesting that they may be part of a larger network regulating antiviral immune responses. In line with this, expression of an LTR12C-SEMA4D fusion transcript is also increased in HIV-1 infected cells (107). SEMA4D (also called CD100) is a regulator of B cell activation and may contribute to T cell senescence in HIV-1 infected individuals (111,112).…”

“…Our knowledge about endogenous retroviral elements involved in cellular immune responses is constantly increasing. Recent key findings include the discovery of retroviral Envs restricting retroviral infection in primates (56,57), the identification of a SUMO-dependent pathway of antiviral immunity that involves sensing of ERV nucleic acids (15), as well as the description of additional retroviral promoter and enhancer elements regulating antiviral gene expression (93,97,107). These reports not only provide important insights into innate antiviral defense mechanisms, but also help to assess the role of ERV activation that is observed in a variety of infectious and non-infectious diseases.…”

“…Another important aspect of future studies will be to decipher the pathways that trigger the activation of specific ERV repeats or families upon viral infection. Are ERVs primarily activated by the cytokine storm in response to viral infection ( 97 (107,110)? Answering these questions will shed light on the ERV-immune network that is activated in response to infection and may uncover strategies that viruses have evolved to evade ERV-mediated immunity.…”