Editing Retrovirus (section)

==Multiplication==
[[File:Life Cycle of a Retrovirus.svg|thumb|upright=2|A retrovirus has a membrane containing glycoproteins, which are able to bind to a receptor protein on a host cell. There are two strands of RNA within the cell that have three enzymes: protease, reverse transcriptase, and integrase (1). The first step of replication is the binding of the glycoprotein to the receptor protein (2). Once these have been bound, the cell membrane degrades, becoming part of the host cell, and the RNA strands and enzymes enter the cell (3). Within the cell, reverse transcriptase creates a complementary strand of DNA from the retrovirus RNA and the RNA is degraded; this strand of DNA is known as cDNA (4). The cDNA is then replicated, and the two strands form a weak bond and enter the nucleus (5). Once in the nucleus, the DNA is integrated into the host cell's DNA with the help of integrase (6). This cell can either stay dormant, or RNA may be synthesized from the DNA and used to create the proteins for a new retrovirus (7). Ribosome units are used to translate the mRNA of the virus into the amino acid sequences which can be made into proteins in the rough endoplasmic reticulum. This step will also make viral enzymes and capsid proteins (8). Viral RNA will be made in the nucleus. These pieces are then gathered together and are pinched off of the cell membrane as a new retrovirus (9).]]
When retroviruses have integrated their own genome into the [[germline|germ line]], their genome is [[inheritance|passed on]] to a following generation. These [[endogenous retrovirus]]es (ERVs), contrasted with [[exogenous DNA|exogenous]] ones, now make up 5–8% of the human genome.<ref>{{cite journal | vauthors = Belshaw R, Pereira V, Katzourakis A, Talbot G, Paces J, Burt A, Tristem M | title = Long-term reinfection of the human genome by endogenous retroviruses | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 14 | pages = 4894–9 | date = April 2004 | pmid = 15044706 | pmc = 387345 | doi = 10.1073/pnas.0307800101 | bibcode = 2004PNAS..101.4894B | doi-access = free }}</ref> Most insertions have no known function and are often referred to as "[[junk DNA]]". However, many endogenous retroviruses play important roles in host biology, such as control of gene transcription, cell fusion during [[placenta]]l development in the course of the [[germination]] of an [[embryo]], and resistance to exogenous retroviral infection. Endogenous retroviruses have also received special attention in the research of [[immunology]]-related pathologies, such as [[autoimmune disease]]s like [[multiple sclerosis]], although endogenous retroviruses have not yet been proven to play any causal role in this class of disease.<ref>{{cite journal | vauthors = Medstrand P, van de Lagemaat LN, Dunn CA, Landry JR, Svenback D, Mager DL | title = Impact of transposable elements on the evolution of mammalian gene regulation | journal = Cytogenetic and Genome Research | volume = 110 | issue = 1–4 | pages = 342–52 | year = 2005 | pmid = 16093686 | doi = 10.1159/000084966 | s2cid = 25307890 }}</ref>

While transcription was classically thought to occur only from DNA to RNA, [[reverse transcriptase]] transcribes RNA into DNA. The term "retro" in retrovirus refers to this reversal (making DNA from RNA) of the usual direction of transcription.  It still obeys the [[central dogma of molecular biology]], which states that information can be transferred from nucleic acid to nucleic acid but cannot be transferred back from protein to either protein or nucleic acid. Reverse transcriptase activity outside of retroviruses has been found in almost all [[eukaryote]]s, enabling the generation and insertion of new copies of [[retrotransposon]]s into the host genome. These inserts are transcribed by enzymes of the host into new RNA molecules that enter the cytosol. Next, some of these RNA molecules are translated into viral proteins. The proteins encoded by the gag and pol genes are translated from genome-length mRNAs into Gag and Gag–Pol polyproteins. In example, for the ''gag'' gene; it is translated into molecules of the capsid protein, and for the ''pol'' gene; it is translated into molecules of reverse transcriptase. Retroviruses need a lot more of the Gag proteins than the Pol proteins and have developed advanced systems to synthesize the required amount of each. As an example, after Gag synthesis nearly 95 percent of the ribosomes terminate translation, while other ribosomes continue translation to synthesize Gag–Pol. In the rough endoplasmic reticulum glycosylation begins and the ''env'' gene is translated from spliced mRNAs in the rough endoplasmic reticulum, into molecules of the envelope protein. When the envelope protein molecules are carried to the Golgi complex, they are divided into surface glycoprotein and transmembrane glycoprotein by a host protease. These two glycoprotein products stay in close affiliation, and they are transported to the plasma membrane after further glycosylation.<ref name=":1" />

It is important to note that a retrovirus must "bring" its own reverse transcriptase in its [[capsid]], otherwise it is unable to utilize the enzymes of the infected cell to carry out the task, due to the unusual nature of producing DNA from RNA.<ref>{{Cite journal |last=Coffin |first=John M. |last2=Fan |first2=Hung |date=2016-09-29 |title=The Discovery of Reverse Transcriptase |url=https://www.annualreviews.org/content/journals/10.1146/annurev-virology-110615-035556 |journal=Annual Review of Virology |language=en |volume=3 |issue= |pages=29–51 |doi=10.1146/annurev-virology-110615-035556 |issn=2327-056X}}</ref>

Industrial drugs that are designed as protease and [[reverse-transcriptase inhibitor]]s are made such that they target specific sites and sequences within their respective enzymes.  However these drugs can quickly become ineffective due to the fact that the gene sequences that code for the protease and the reverse transcriptase quickly mutate. These changes in bases cause specific codons and sites with the enzymes to change and thereby avoid drug targeting by losing the sites that the drug actually targets.{{citation needed|date=November 2022}}

Because reverse transcription lacks the usual [[Proofreading (biology)|proofreading]] of DNA replication, a retrovirus [[mutate]]s very often. This enables the virus to grow [[immunology|resistant]] to antiviral pharmaceuticals quickly, and impedes the development of effective [[vaccines]] and inhibitors for the retrovirus.<ref>{{cite journal | vauthors = Svarovskaia ES, Cheslock SR, Zhang WH, Hu WS, Pathak VK | title = Retroviral mutation rates and reverse transcriptase fidelity | journal = Frontiers in Bioscience | volume = 8 | issue = 1–3 | pages = d117–34 | date = January 2003 | pmid = 12456349 | doi = 10.2741/957 | doi-access = free }}</ref>

One difficulty faced with some retroviruses, such as the Moloney retrovirus, involves the requirement for cells to be actively dividing for transduction. As a result, cells such as neurons are very resistant to infection and transduction by retroviruses. This gives rise to a concern that insertional mutagenesis due to integration into the host genome might lead to cancer or leukemia. This is unlike ''[[Lentivirus]]'', a genus of ''Retroviridae'', which are able to integrate their RNA into the genome of non-dividing host cells.{{citation needed|date=November 2022}}

===Recombination===

Two [[RNA]] [[genome]]s are packaged into each retrovirus particle, but, after an infection, each virus generates only one [[provirus]].<ref name = Rawson2018>{{cite journal | vauthors = Rawson JM, Nikolaitchik OA, Keele BF, Pathak VK, Hu WS | title = Recombination is required for efficient HIV-1 replication and the maintenance of viral genome integrity | journal = Nucleic Acids Research | volume = 46 | issue = 20 | pages = 10535–10545 | date = November 2018 | pmid = 30307534 | pmc = 6237782 | doi = 10.1093/nar/gky910 }}</ref>  After infection, [[reverse transcriptase|reverse transcription]] occurs and this process is accompanied by [[homologous recombination|recombination]].  Recombination involves template strand switching between the two genome copies (copy choice recombination) during reverse transcription.  From 5 to 14 recombination events per genome occur at each replication cycle.<ref name="pmid26691546">{{cite journal | vauthors = Cromer D, Grimm AJ, Schlub TE, Mak J, Davenport MP | title = Estimating the in-vivo HIV template switching and recombination rate | journal = AIDS | volume = 30 | issue = 2 | pages = 185–92 | date = January 2016 | pmid = 26691546 | doi = 10.1097/QAD.0000000000000936 | s2cid = 20086739 | doi-access = free }}</ref>  Genetic recombination appears to be necessary for maintaining genome integrity and as a repair mechanism for salvaging damaged genomes.<ref name = Rawson2018/>