ERVs have been found to be associated to disease not only through disease-causing relations, but also through immunity. The frequency of ERVs in long terminal repeats (LTRs) likely correlates to viral adaptations to take advantage of immunity signaling pathways that promote viral transcription and replication. A study done in 2016 investigated the benefit of ancient viral DNA integrated into a host through gene regulation networks induced by interferons, a branch of innate immunity. These cytokines are first to respond to viral infection and are also important in immunosurveillance for malignant cells. ERVs are predicted to act as cis-regulatory elements, but much of the adaptive consequences of this for certain physiological functions is still unknown. There is data that supports the general role of ERVs in the regulation of human interferon response, specifically to interferon-gamma (IFNG). For example, interferon-stimulated genes were found to be greatly enriched with ERVs bound by signal transducer and activator of transcription 1 (STAT1) and/or Interferon regulatory factor (IRF1) in CD14+ macrophages.
HERVs also play various roles shaping the human innate immunity response, with some sequences activating the system and others suppressing it. They may also protect from exogenous retroviral infections: the virus-like transcripts can activate pattern recognition receptors, and the proteins can interfere with active retroviruses. A gag protein from HERV-K(HML2) is shown to mix with HIV Gag, impairing HIV capsid formation as a result.