By Jared Stern
Retroviruses (Retroviridae) are a family of viruses first discovered at the start of the 20th century1, even though they have existed for nearly half a billion years2. These viruses are all enveloped. This means they are surrounded by a lipid layer that they acquire from the host cell when new viral particles bud off from the cell3. For more information on the build of these viruses read our earlier article on the life cycle of HIV. Retroviridae are biologically unique as they go against the central dogma of molecular biology which states that there is a one-way progression of genetic information from DNA to RNA to protein – hence the “retro” prefix to their name4. This is because the genetic makeup of a retrovirus is RNA (rather than DNA) and upon infection, this genome becomes reverse transcribed into DNA5.
Retroviruses can be broadly classified as simple or complex, depending on their genetic organization.4 All of the viruses contain three genes; Gag, Pol, and Env which encode structural proteins of the virus – i.e. proteins that are present in the infectious viral particle. Gag encodes proteins that make up the internal physical structure of the virus; matrix, capsid, and nucleoprotein. The gene Pol encodes the enzymatic proteins; reverse transcriptase, integrase, and protease. Protease is important in enzymatic cleavage of newly formed viruses to become fully mature and infectious. Integrase also is responsible for a key step in the viruses replication cycle – the integration of the retroviral DNA genome into the host cell genome6. This step is the reason why infection with retroviruses endures for the life of the infected organism. The final shared gene is env which encodes the envelope proteins on the surface of the virus7.
Complex retroviruses also have these three main genes but they differ from simple retroviruses by having additional structural and non-structural/accessory genes that regulate replication at multiple steps both pre- and post-integration8. There are three main types of retroviruses that infect humans; Human Immunodeficiency Virus (HIV), Human T-cell Leukemia Virus (HTLV) and Human Foamy Virus (HFV) - all of which are complex retroviruses. Approximately 37 million people worldwide are living with HIV and it is the causative agent of Acquired Immune Deficiency Syndrome (AIDS) 9,10. HTLV was the first human exogenous retrovirus discovered and approximately five to ten million people are living with HTLV-111, 12. Conversely, whilst cases of HFV infection have occurred, these have all been a result of zoonotic infection from primates to humans and no human-to-human transmission has been shown13, 14.
Similar to HFV, HIV has seen multiple independent zoonoses with HIV-1 being most similar to simian immunodeficiency virus (SIV) in chimpanzees, and HIV-2 having arisen from sooty mangabey monkeys15, 16. Analyses have shown that the pandemic strain of HIV has existed since around 1920.15 HTLV also has genetic similarities to simian T-cell leukemia virus (STLV) and although its origins are less certain than HIV’s, it is clear HTLV has existed for far longer than HIV, with estimates indicating that some strains having arisen more than 20,000 years ago17, 18.
In addition to infectious retroviruses that are transmitted horizontally or vertically to new organisms, there is an abundance of endogenous retroviruses19. These retroviruses have at some point in history had their genome integrated into their host’s germline cells (cells that give rise to eggs and sperm) 19,20. This means that these endogenous retroviruses (ERVs) are inherited by the host’s offspring as any genetic information would during sexual reproduction. This is by no means a rare event since approximately 5-8% of the human genome is made up of ERVs21 and studies have estimated that ERVs have existed for at least 140 million years22. Although most of these ancient ERVs are inactive, newly endogenised retroviruses such as the Koala retrovirus still produce infectious virions23 and, experimentally, integrated SIV proviruses have been found in the ovaries of infected macaques24.
1 Rous P. A Sarcoma Of The Fowl Transmissible By An Agent Separable From The Tumor Cells. J Exp Med 1911; 13:397-411.
2 Aiewsakun P, Katzourakis A. Marine origin of retroviruses in the early Palaeozoic Era. Nature Communications 2017; 8:13954.
3 Waheed AA, Freed EO. The Role of Lipids in Retrovirus Replication. Viruses 2010; 2:1146-80.
4 Coffin JM, Hughes SH, Varmus HE, Editors. The Place of Retroviruses in Biology. In: Retroviruses. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 1997.
5 Temin HM, Mizutani S. Viral RNA-dependent DNA polymerase: RNA-dependent DNA polymerase in virions of Rous sarcoma virus. Nature 1970; 226:1211-3.
6 Brown PO, Bowerman B, Varmus HE, Bishop JM. Retroviral integration: structure of the initial covalent product and its precursor, and a role for the viral IN protein. Proc Natl Acad Sci U S A 1989; 86:2525-9.
7 Coffin JM, Hughes SH, Varmus HE, Editors. Genetic Organization. In: Retroviruses.
8 Burrell CJ, Howard CR, Murphy FA. Chapter 23 - Retroviruses. In: Fenner and White's Medical Virology (Fifth Edition). London: Academic Press; 2017: 317-44.
9 UNAIDS. UNAIDS Data 2017. 2017.
10 Barre-Sinoussi F, Chermann J, Rey F, Nugeyre M, Chamaret S, Gruest J, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983; 220:868-71.
11 Gessain A, Gessain A, Cassar O. Epidemiological Aspects and World Distribution of HTLV-1 Infection. Frontiers in Microbiology 2012; 3.
12 Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proceedings of the National Academy of Sciences of the United States of America 1980; 77:7415-9.
13 Brooks JI, Rud EW, Pilon RG, Smith JM, Switzer WM, Sandstrom PA. Cross-species retroviral transmission from macaques to human beings. The Lancet 2002; 360:387-8.
14 Betsem E, Rua R, Tortevoye P, Froment A, Gessain A. Frequent and Recent Human Acquisition of Simian Foamy Viruses Through Apes' Bites in Central Africa. PLOS Pathogens 2011; 7:e1002306.
15 Faria NR, Rambaut A, Suchard MA, Baele G, Bedford T, Ward MJ, et al. The early spread and epidemic ignition of HIV-1 in human populations. Science 2014; 346:56-61.
16 Sharp PM, Hahn BH. Origins of HIV and the AIDS pandemic. Cold Spring Harb Perspect Med 2011; 1:a006841.
17 Cassar O, Einsiedel L, Afonso PV, Gessain A. Human T-Cell Lymphotropic Virus Type 1 Subtype C Molecular Variants among Indigenous Australians: New Insights into the Molecular Epidemiology of HTLV-1 in Australo-Melanesia. PLOS Neglected Tropical Diseases 2013; 7:e2418.
18 Van Dooren S, Salemi M, Vandamme AM. Dating the Origin of the African Human T-Cell Lymphotropic Virus Type-I (HTLV-I) Subtypes. Molecular Biology and Evolution 2001; 18:661-71.
19 Weiss RA. The discovery of endogenous retroviruses. Retrovirology 2006; 3:67.
20 Johnson WE. Endogenous Retroviruses in the Genomics Era. Annual Review of Virology 2015; 2:135-59.
21 Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature 2001; 409:860-921.
22 Lee A, Nolan A, Watson J, Tristem M. Identification of an ancient endogenous retrovirus, predating the divergence of the placental mammals. Philosophical Transactions of the Royal Society B: Biological Sciences 2013; 368.
23 Tarlinton R, Meers J, Young P. Endogenous retroviruses. Cellular and Molecular Life Sciences 2008; 65:3413-21.
24 Stieh DJ, Maric D, Kelley ZL, Anderson MR, Hattaway HZ, Beilfuss BA, et al. Vaginal Challenge with an SIV-Based Dual Reporter System Reveals That Infection Can Occur throughout the Upper and Lower Female Reproductive Tract. PLOS Pathogens 2014; 10:e1004440.