The second chance story of HIV-1 DNA: Unintegrated? Not a problem!

Wu, Yuntao

doi:10.1186/1742-4690-5-61

Cited by 23 publications

(28 citation statements)

References 36 publications

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“…In experimentally infected CD4 ϩ T cells, unintegrated DNA is in vast excess of integrated proviruses (279). When present on their own, unintegrated HIV-1 DNAs tend to express only spliced RNAs due to low levels of Rev (348). However, a recent report suggested that unintegrated DNAs can complement defective integrated HIV-1 (108).…”

mentioning

confidence: 97%

The Remarkable Frequency of Human Immunodeficiency Virus Type 1 Genetic Recombination

Onafuwa-Nuga

Telesnitsky

2009

Microbiol Mol Biol Rev

147

172

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SUMMARY The genetic diversity of human immunodeficiency virus type 1 (HIV-1) results from a combination of point mutations and genetic recombination, and rates of both processes are unusually high. This review focuses on the mechanisms and outcomes of HIV-1 genetic recombination and on the parameters that make recombination so remarkably frequent. Experimental work has demonstrated that the process that leads to recombination—a copy choice mechanism involving the migration of reverse transcriptase between viral RNA templates—occurs several times on average during every round of HIV-1 DNA synthesis. Key biological factors that lead to high recombination rates for all retroviruses are the recombination-prone nature of their reverse transcription machinery and their pseudodiploid RNA genomes. However, HIV-1 genes recombine even more frequently than do those of many other retroviruses. This reflects the way in which HIV-1 selects genomic RNAs for coencapsidation as well as cell-to-cell transmission properties that lead to unusually frequent associations between distinct viral genotypes. HIV-1 faces strong and changeable selective conditions during replication within patients. The mode of HIV-1 persistence as integrated proviruses and strong selection for defective proviruses in vivo provide conditions for archiving alleles, which can be resuscitated years after initial provirus establishment. Recombination can facilitate drug resistance and may allow superinfecting HIV-1 strains to evade preexisting immune responses, thus adding to challenges in vaccine development. These properties converge to provide HIV-1 with the means, motive, and opportunity to recombine its genetic material at an unprecedented high rate and to allow genetic recombination to serve as one of the highest barriers to HIV-1 eradication.

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confidence: 97%

The Remarkable Frequency of Human Immunodeficiency Virus Type 1 Genetic Recombination

Onafuwa-Nuga

Telesnitsky

2009

Microbiol Mol Biol Rev

147

172

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“…Three species of unintegrated HIV cDNAs are found in natural infections; these are linear reverse-transcribed cDNA, which is the template for integration, and 1-long terminal repeat (LTR) and 2-LTR circular forms, which are the products of autointegration or nonhomologous recombination and nonhomologous end-joining events of linear cDNAs, respectively (15,26,37). The circular cDNAs were long considered to be "dead end" products, which cannot serve as templates for integration, though it is now understood that unintegrated cDNA can be complemented by superinfecting virus to yield productive infection (17,39,53).…”

mentioning

confidence: 99%

“…This process enables transcription and translation of viral genes by host cells, ultimately resulting in new viral progeny. However, human immunodeficiency virus type 1 (HIV-1) gene transcription and translation can also occur prior to, or even in the absence of, viral integration (8,53,57), since unintegrated, reverse-transcribed viral cDNAs can also serve as a template for transcription (22). Three species of unintegrated HIV cDNAs are found in natural infections; these are linear reverse-transcribed cDNA, which is the template for integration, and 1-long terminal repeat (LTR) and 2-LTR circular forms, which are the products of autointegration or nonhomologous recombination and nonhomologous end-joining events of linear cDNAs, respectively (15,26,37).…”

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confidence: 99%

Transcription of Preintegrated HIV-1 cDNA Modulates Cell Surface Expression of Major Histocompatibility Complex Class I via Nef

Sloan

Kuhl

Donahue

et al. 2011

J Virol

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“…1a(i) and see Butler et al, 2001;Levin et al, 2009a]. Infection with both viruses leads to the appearance of unintegrated viral cDNA which promotes the expression of several viral proteins, among them Rev (Iyer et al, 2009;Kelly et al, 2008;Wu, 2004Wu, , 2008Wu & Marsh, 2003 and Fig. 1b).…”

Section: Sir Can Be Promoted By Rev Expressed From Unintegrated Cdnamentioning

confidence: 99%

“…Several studies have clearly demonstrated that no direct relations exist between SIR and CD4 downregulation (Potash & Volsky, 1998;Saha et al, 1999;Volsky et al, 1996). Even assuming that downregulation of CD4 contributes to the development of SIR, the possibility of additional, CD4-independent mechanisms cannot be excluded and have, in fact, been suggested (Potash & Volsky, 1998;Wildum et al, 2006 Similar to Nef, the Rev protein is present in the early phase of infection, expressed from unintegrated viral cDNA (Iyer et al, 2009;Kelly et al, 2008;Wu, 2004Wu, , 2008Wu & Marsh, 2003). The late viral Rev encoded by the integrated HIV genome has so far been implicated mainly in promoting nuclear export of unspliced and single-spliced transcripts (Pollard & Malim, 1998).…”

Section: Introductionmentioning

confidence: 99%

A novel role for the viral Rev protein in promoting resistance to superinfection by human immunodeficiency virus type 1

Levin

Hayouka

Friedler

et al. 2010

Journal of General Virology

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At the cellular level, cells infected with human immunodeficiency virus type 1 (HIV-1) exhibit immunity to a second infection by the virus that initiated the first infection or by related viruses [superinfection resistance (SIR)]. In the case of HIV infection, SIR was basically attributed to downregulation of the CD4 receptors. We have recently reported on an interaction between HIV-1 Rev and integrase (IN) proteins, which results in inhibition of IN activity in vitro and integration of cDNA in HIV-1-infected cells. A novel function for the viral Rev protein in controlling integration of HIV cDNAs was thus proposed. The results of the present work suggest involvement of the inhibitory Rev in sustaining SIR. A single exposure to wild-type HIV-1 resulted in one to two integrations per cell. The number of integrated proviral cDNA copies remained at this low level even after double infection or superinfection. SIR was dependent on Rev expression by the strain used for the first infection and was eliminated by peptides that disrupt intracellular complex formation between IN and Rev. The same lack of resistance was observed in the absence of Rev, namely following first infection with a DRev HIV strain. The involvement of Rev, expressed from either unintegrated or integrated viral cDNA, in promoting SIR was clearly demonstrated. We conclude that SIR involves Rev-dependent control of HIV cDNA integration.

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The second chance story of HIV-1 DNA: Unintegrated? Not a problem!

Cited by 23 publications

References 36 publications

The Remarkable Frequency of Human Immunodeficiency Virus Type 1 Genetic Recombination

The Remarkable Frequency of Human Immunodeficiency Virus Type 1 Genetic Recombination

Transcription of Preintegrated HIV-1 cDNA Modulates Cell Surface Expression of Major Histocompatibility Complex Class I via Nef

A novel role for the viral Rev protein in promoting resistance to superinfection by human immunodeficiency virus type 1

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