Endogenous retroviral pathogenesis in lupus

Abstract

Purpose of review: 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.

Recent findings: 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.

Summary: 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.

Figure 1. Schematic diagram of endogenous retrovirus-mediated mechanisms of pathogenesis in lupus

(a) Effect of ERV on autoimmunity via structural molecular mimicry, cis-activation, trans-activation, and receptor recycling. As an example, the HRES-1 LTR contains TATA box, poly-adenylation (polyA) site, tRNA primer-binding site (PBS), an HIV-1 trans-activation region (TAR), and inverted repeats (IR) at typical locations [49]. Transcription from the HRES-1 LTR may be stimulated by trans-acting factors, e.g. tat of HIV-1 [50]. ERV proteins may interfere with virion assembly or recycling of cell surface receptors, such as CD4 cell, thus effecting replication, infectivity, and pathogenicity of exogenous viruses [50]. HRES-1/Rab4 also regulates the recycling of the CD3/TCRζ chain [51•]. (b) ERV and L1 elements are reverse-transcribed into DNA which is in turn degraded by Trex1 [52]. Deficiency of (Trex1) has been associated with Aicardi-Goutieres syndrome (AGS) and chilblain lupus [53,54].