Genetic and environmental factors influence the development of systemic lupus erythematosus (SLE). Endogenous retroviruses (ERVs) are proposed as a molecular link between the human genome and environmental factors, such as viruses, in lupus pathogenesis.The HRES-1 human ERV encodes a 28-kD nuclear autoantigen and a 24-kD small GTP-ase, termed HRES-1/Rab4. HRES-1/p28 is a target of cross-reactive antiviral antibodies, whereas HRES-1/Rab4 regulates the surface expression of CD4 via endosome recycling. The tat gene of HIV-1 induces the expression of HRES-1/Rab4, which in turn downregulates expression of CD4 and susceptibility to reinfection by HIV-1. HRES-1/Rab4 is overexpressed in lupus T cells where it correlates with increased recycling of CD4 and CD3 and contributes to downregulation of CD3/TCRzeta via lysosomal degradation. Chilblain lupus has been linked to the deficiency of 3'-5' repair exonuclease Trex1 that metabolizes DNA reverse-transcribed from ERV. Trex1 deficiency or blocked integration of ERV-encoded DNA also promotes lupus in murine models.ERV proteins may trigger lupus through structural and functional molecular mimicry, whereas the accumulation of ERV-derived nucleic acids stimulates interferon and anti-DNA antibody production in SLE.