Retroviruses, reverse transcription

The human immunodeficiency vims (HIV) is the causative agent of the acquired immunodeficiency syndrome (AIDS). HIV is a retrovirus, whose replication includes the transcription of the single-stranded RNA genome into double stranded DNA (reverse transcription) and the covalent insertion of the DNA... 

Reverse transcription is the copying of an RNA molecule back into its DNA complement. The enzymes that perform this function are called reverse transcriptases. Reverse transcription is used naturally by retroviruses to insert themselves into an organism s genome. Artificially induced reverse transcription is a useful technique for translating unstable messenger RNA (mRNA) molecules into stable cDNA. 

Lawrence DM, Durham LC, Schwartz L, Seth P, Marie D, Major EO (2004) Human immunodeficiency virus type 1 infection of human brain-derived progenitor cells. J Virol 78(14) 7319-7328 Li XY, Guo F, Zhang L, Kleiman L, Cen S (2007) APOBEC3G inhibits DNA strand transfer during HIV-1 reverse transcription. J Biol Chem 282(44) 32065-32074 Lin J, Cullen BR (2007) Analysis of the interaction of primate retroviruses with the human RNA interference machinery. J Virol 81(22) 12218-12226 Liu JO (2005) The yins of T cell activation. Sci STKE 2005(265) rel... 

If the virus has double-stranded RNA (ds RNA), this RNA serves as a template in a manner analogous to DNA. There are three classes of viruses with ss RNA and they differ in the mechanism by which mRNA is synthesized. In the simplest case, the incoming viral RNA is the plus sense and hence serves directly as mRNA, and copies of this viral RNA are also copied to make further mRNA molecules. In another class, the viral RNA has a minus (-) sense. In such viruses a copy is made (plus sense) and this copy becomes the mRNA. In the case of the retroviruses (causal agents of certain kinds of cancers and AIDS), a new phenomenon called reverse transcription is seen, in which virion ss RNA is copied to a double-stranded DNA (through a ss DNA intermediate) and the ds DNA then serves as the template for mRNA synthesis (thus ss RNA ss DNA ds DNA). Retrovirus replication is of unusual interest and complexity. 

Reverse transcription, which produces DNA copies of an RNA, is more commonly associated with life cycles of retroviruses, which replicate and express their genome through a DNA intermediate (an integrated provirus). Reverse transcription also occurs to a limited extent in human cells, where it plays a role in amplifying certain highly repetitive sequences in the DNA (Chapter 7). 

Discussion of the original proposal for reverse transcription in retroviruses. 

Transposition of DNA, which is discussed in Chapter 27, Section D,4, may seem to be a rare and relatively unimportant event in our body cells. However, transposon DNA accounts for 35% or more of the human genome740 and apparently plays a major role in evolution. Like other transposons, the DNA sequences known as retrotransposons also move about within DNA. However, they use an indirect mechanism that involves synthesis of mRNA and reverse transcription.740 741 The reverse transcribed complementary DNA may be inserted back into the genome at new locations. The necessary chemical reactions parallel those involved in the replication of retroviruses (Fig. 28-23, 28-24). Retrotransposens, truncated retrotransposons, and related sequences constitute as much as 16% of the human genome.741... 

Reverse transcription (which occurs in both prokaryotes and eukaryotes) is the synthesis of DNA from an RNA template. A class of RNA viruses, called retroviruses, are characterized by the presence of an RNA-dependent DNA polymerase (reverse transcriptase). The vims that causes AIDS, Human Immunodeficiency Virus (HIV), is a retro-vims. Because nuclear cell division doesn t use reverse transcriptase, the most effective anti-HIV drugs target reverse transcriptase, either its synthesis or its activity. Telomerase, discussed in the previous section, is a specialized reverse transcriptase enzyme. See Figure 12-5. 

All of the mammalian transposable elements that have been characterized to date seem to be the result of transpositions that proceeded through an RNA intermediate. This process is known as retrotransposition or retroposition. Three classes of these retrotransposable elements are known in mammals (1) SINEs, or short interspersed repeated sequences such as the human Alu family and rodent Bl (2) LINEs, or long interspersed repeated sequences such as LI in a variety of mammalian species and (3) retrovirus-like elements, such as THE 1 in humans and mys and IAP in rodents. Retrovirus-like elements have long terminal repeats (LTRs) that often surround two open reading frames (ORFs) like those of retroviruses, but they lack the ability to leave one cell and enter another. LINEs also have two ORFs, but have no LTRs. SINEs have no LTRs and no ORFs. Transposition of all of these elements must involve reverse transcription of the RNA intermediate in some cases the required reverse transcriptase is apparently encoded by the element itself. 

The major direction of information flow in biological systems is from DNA to RNA to protein. However, there are instances in which RNA is copied into a complementary DNA strand by the process dubbed reverse transcription by the enzyme known as the reverse transcriptase . This mechanism is used by retroviruses including the HIV virus, whose infectious particles contain RNA as the genetic material. The virus particles contain a virally encoded reverse transcriptase which, following infection, copies the viral RNA into DNA. The resultant DNA copy is incorporated into the genome of the infected cell. 

Reverse transcription and nuclear translocation of the preintegration complex are thought to be limiting steps in retroviral transduction, especially in terminally differentiated postmitotic cells. Proviral DNA synthesis of all retroviruses depends strongly on cellular conditions, and low nucleoside pools or absence of cellular cofactors may explain the incomplete reverse transcription in quiescent or stationary cells (56, 65-70). 

Retrovirus A virus in which the genetic material located in the virus is RNA. The genetic information in the retrovirus must be converted to DNA in the host by the process of reverse transcription. 

After a retrovirus Infects a cell, reverse transcription of Its RNA genome by the retrovirus-encoded reverse transcriptase yields a double-stranded DNA containing complete LTRs (Figure 10-13). Integrase, another enzyme encoded by retroviruses that Is closely related to the trans-posase of some DNA transposons, uses a similar mechanism to Insert the double-stranded retroviral DNA Into the hostcell genome. In this process, short direct repeats of the target-site sequence are generated at either end of the Inserted viral DNA sequence. 

I he virus that is responsible for the acquired immune deficiency syndrome (AIDS) is called the human immunodeficiency virus, or HIV. HIV is a member of a family of viruses called retroviruses, all of which have single-stranded RNA as their genetic material. The RNA is copied by a viral enzyme called reverse transcriptase into a double-stranded DNA molecule. This process is the opposite of the central dogma, which states that the flow of genetic information is from DNA to RNA. But these viruses reverse that flow, RNA to DNA. For this reason these viruses are called retroviruses, which literally means "backward viruses." The process of producing a DNA copy of the RNA is called reverse transcription. 

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