What are Retroviruses?
Retroviruses are viruses that insert their DNA copy of their RNA genome into the DNA of the host cell they have invaded, resulting in changes in the cell’s DNA. Retroviruses basically use the host cells’ DNA to integrate themselves and use the cell’s machinery for replication1.
What is an Endogenous Retrovirus?
Endogenous Retroviruses (ERVs) are retroviruses that over the course of evolution have integrated into germ line cells and eventually became part of the host genome.
If a retrovirus infects a germline cell, the viral DNA becomes endogenous to the hosts’ DNA. Resulting in the copy of the viral DNA is present in every cell of the descendants.
Human Endogenous Retroviruses
Human Endogenous Retroviruses (HERVs) are families of retroviruses in our genome, similar to present-day exogenous retroviruses such as Human Immunodeficiency Virus (HIV) and Human T-lymphotropic virus type-1 (HTLV)1.
Human Endogenous Retroviruses have been inherited by successive generations. 5%- 8% of human DNA is composed of remnant copies of viruses which had contaminated our ancestors. Our DNA contains over 30 families of HERVs. Although some of them have high biological benefits, studies show that various numbers of HERVs have been linked with certain cancers and autoimmune diseases2.
In the past few years, It has been clearly acquired that one group termed HERV-K plays a critical role in embryogenesis. HERV-K has multiple copies in the human genome and some of them have complete open reading frames that are transcribed and translated, especially in embryogenesis. HERV-K is considered a supergroup of viruses. Being one of the subtypes, HML-2 is considered to be the most active one. Abnormal expression of HML-2 in adult tissues has been linked with certain types of cancer and neurodegenerative diseases3,4.
It has been thought that HML-2 is only reactivated under pathological conditions. However, HERVs are consistently expressed at low levels in every human tissue that has been studied and may even provide potential benefits to their hosts.
Benefits of HERVs
Antiviral Defense
Viral infections of a cell prevent infection from other related viruses5,6. Therefore, it has been suggested that ERVs have cooperated with vertebrates to protect them against infections of related exogenous retroviruses. For example, expression of the Envelope protein of the FV-4 ERV on the surface of Mouse cells competes for the receptors of related viruses, preventing them from entering the cell2,7.
Placenta Formation
The most peculiar physiological function of HERVs is the involvement of the Envelope proteins in the formation of the placenta, where they become highly expressed8.
Syncytin-1 and Syncytin-2, which are the Envelope proteins of HERV-W and HERV-FRD, respectively, have preserved fusogenic capacity that allows the formation of the syncytiotrophoblast layer and its junction with the cytotrophoblast2,8.
Pathological Conditions
HERVs and Cancer
It has been known that some retroviruses can cause cancer since the discovery that the Rous sarcoma virus causes sarcoma in chickens2,9. Other well-known onco-retroviruses are HTLV-1 and MMTV. HTLV-1, which causes adult T-cell lymphoma in 2-7% of infected individuals9. MMTV, which causes mammary tumours in mice and is also a beta-retrovirus that can be carried endogenously like HML-29. HML-2 has also been linked to cancer development, as its expression has been associated with many cancer types such as teratocarcinoma, germ cell tumours, melanoma, and ovarian and prostate cancer4,9.
HERVs and Neurological Diseases
The evidence for the role of HML-2 in the pathophysiology of sporadic ALS is strong. Several groups have identified the presence of RT activity in the blood and cerebrospinal fluid of patients with ALS. HML-2 gene products gag, pol, and env can be detected in the brains of ALS patients, and the proteins RT and Env are expressed in cortical neurons. This expression was specific for ALS since it could not be found in patients with Parkinson’s or Alzheimer’s disease.
Further evidence is available from rare cases of HIV-infected patients who also develop ALS. HIV infection has been associated with an increase in HML-2 levels. When HIV-ALS patients were treated with antiretroviral drugs early in the course of neurologic manifestations, ALS symptoms were reversed or slowed in a subset of patients. In addition to ALS, activation of HML-2 and polymorphisms of HERV-K18 and K115 have also been associated with schizophrenia2,3,10.
HERVs and HIV
It is known that HIV infection can increase HML-2 mRNA levels in PBMCs and the activation of specific HML-2 genomic loci can be cell-type specific. However, the extent of HML-2 induction in HIV infection remains unclear.
Several studies have found that HML-2 RNA is readily detectable in the plasma of HIV-infected individuals. Regarding the impact of HML-2 on HIV pathogenesis, it is not clear whether HML-2 expression contributes to the control of HIV or whether it enhances viral pathogenicity.
Several groups have reported T-cell responses to HML-2 in HIV-infected patients that are associated with better virologic control and higher T-cell counts. Collectively, these results suggest that HML-2 transcripts induced by HIV infection may be translated into viral proteins that can generate a humoral and/or cytotoxic T-cell response11,12.
References:
- Magiorkinis, G., Blanco-Melo, D. & Belshaw, R. The decline of human endogenous retroviruses: Extinction and survival. Retrovirology 12, (2015).
- Garcia-Montojo, M., Doucet-O’Hare, T., Henderson, L. & Nath, A. Human endogenous retrovirus-K (HML-2): a comprehensive review. Crit Rev Microbiol 44, 715–738 (2018).
- Li, W. et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med 7, (2015).
- Wildschutte, J., … D. R.- & 2014, undefined. The distribution of insertionally polymorphic endogenous retroviruses in breast cancer patients and cancer-free controls. retrovirology.biomedcentral.com.
- Moelling, K., of, F. B.-A. of the N. Y. A. & 2015, undefined. The reverse transcriptase–RNase H: from viruses to antiviral defense. Wiley Online Library 1341, 126–135 (2015).
- Schmidt, N. et al. An influenza virus-triggered SUMO switch orchestrates co-opted endogenous retroviruses to stimulate host antiviral immunity. Proc Natl Acad Sci U S A 116, 17399–17408 (2019).
- Henzy, J. E., Gifford, R. J., Johnson, W. E. & Coffin, J. M. A Novel Recombinant Retrovirus in the Genomes of Modern Birds Combines Features of Avian and Mammalian Retroviruses. J Virol 88, 2398–2405 (2014).
- Lokossou, A., Toudic, C., Viruses, B. B.- & 2014, undefined. Implication of human endogenous retrovirus envelope proteins in placental functions. mdpi.com 6, 4609–4627 (2014).
- Grant, R. et al. Identification of novel simian endogenous retroviruses that are indistinguishable from simian retrovirus (SRV) on current SRV diagnostic assays. Wiley Online Library 46, 158–161 (2017).
- Alfahad, T., research, A. N.-A. & 2013, undefined. Retroviruses and amyotrophic lateral sclerosis. Elsevier.
- Michaud, H., SenGupta, D., … M. D. M.-T. J. of & 2014, undefined. Cutting edge: an antibody recognizing ancestral endogenous virus glycoproteins mediates antibody-dependent cellular cytotoxicity on HIV-1–infected cells. journals.aai.org.
- Michaud, H. A. et al. Trans-activation, post-transcriptional maturation, and induction of antibodies to HERV-K (HML-2) envelope transmembrane protein in HIV-1 infection. Retrovirology 11, (2014).
Inspector: Nadir KERESTECİ
