Higher Selection Pressure from Antiretroviral Drugs in Vivo Results in Increased Evolutionary Distance in HIV-1 pol

Günthard, Huldrych F.; Leigh-Brown, Andrew J.; D’Aquila, Richard T.; Johnson, Victoria A.; Kuritzkes, Daniel R.; Richman, Douglas D.; Wong, Joseph K.

doi:10.1006/viro.1999.9774

Cited by 29 publications

(19 citation statements)

References 42 publications

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“…Because two different defective retroviruses can recombine to form infectious virus, even defective genomes can contribute to the reemergence of dormant genetic information. Intrapatient recombination between circulating strains and archived proviruses contributes to the dynamics of drug resistance and may contribute to the evolution of the coreceptor switch as well (47,118,212,235,271). It is likely that the extent of recombination between variants that arise within an individual has been underappreciated because of the similarity of parental strains (117).…”

Section: Recombination and The Implications Of Proviral Persistencementioning

confidence: 99%

“…(Hypermutation may be an exception to this rule, although whether such mutations imbedded in less altered genome regions result more frequently from recombination or from the limited processivity of mutagenic factors remains unclear [48,222,236].) Some instances of phenotypic switch, including coreceptor switch and reacquisition of drug resistance, have been linked to mutations embedded in localized sequences that differ significantly from flanking sequences, thus providing evidence for recombination within individual patients' virus populations (118,212,235,271).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Recombination and The Implications Of Proviral Persistencementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Remarkable Frequency of Human Immunodeficiency Virus Type 1 Genetic Recombination

Onafuwa-Nuga

Telesnitsky

2009

Microbiol Mol Biol Rev

147

172

View full text Add to dashboard Cite

show abstract

“…The large number (Ͼ50) and high prevalence of circulating recombinant forms (CRFs) demonstrate the evolutionary success of HIV-1 recombinants on a global scale (27). Recombination within individual patients has been documented in numerous studies (reviewed in reference 25), and recombination involving drug-resistant viruses provides a mechanism for the spread of drug resistance throughout a patient's quasispecies (28)(29)(30). Since the latent reservoir represents an archive of the history of a patient's quasispecies, including viruses with any previously existing drug resistance mutations (11)(12)(13)(14)(15), latent viruses represent an important source for the further generation of genetic diversity under selective pressure.…”

mentioning

confidence: 99%

Latent HIV-1 Can Be Reactivated by Cellular Superinfection in a Tat-Dependent Manner, Which Can Lead to the Emergence of Multidrug-Resistant Recombinant Viruses

Donahue

Bastarache

Sloan

et al. 2013

J Virol

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bThe HIV-1 latent reservoir represents an important source of genetic diversity that could contribute to viral evolution and multidrug resistance following latent virus reactivation. This could occur by superinfection of a latently infected cell. We asked whether latent viruses might be reactivated when their host cells are superinfected, and if so, whether they could contribute to the generation of recombinant viruses. Using populations of latently infected Jurkat cells, we found that latent viruses were efficiently reactivated upon superinfection. Pathways leading to latent virus reactivation via superinfection might include gp120-CD4/CXCR4-induced signaling, modulation of the cellular environment by Nef, and/or the activity of Tat produced upon superinfection. Using a range of antiviral compounds and genetic approaches, we show that gp120 and Nef are not required for latent virus reactivation by superinfection, but this process depends on production of functional Tat by the superinfecting virus. In a primary cell model of latency in unstimulated CD4 T cells, superinfection also led to latent virus reactivation. Drug-resistant latent viruses were also reactivated following superinfection in Jurkat cells and were able to undergo recombination with the superinfecting virus. Under drug-selective pressure, this generated multidrug-resistant recombinants that were identified by unique restriction digestion band patterns and by population-level sequencing. During conditions of poor drug adherence, treatment interruption or treatment failure, or in drug-impermeable sanctuary sites, reactivation of latent viruses by superinfection or other means could provide for the emergence or spread of replicatively fit viruses in the face of strong selective pressures.

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“…More importantly, recombination appears to be an essential mechanism for retroviral survival. It allows viruses to repair genomic errors (8 -11) and to combine resistance markers against anti-retroviral drugs (12)(13)(14), and it promotes genomic shuffling that frustrates immune surveillance and allows for the emergence of new mosaic viral strains (15,16).…”

mentioning

confidence: 99%

Role of the Reverse Transcriptase, Nucleocapsid Protein, and Template Structure in the Two-step Transfer Mechanism in Retroviral Recombination

Roda

Balakrishnan

Hanson

et al. 2003

Journal of Biological Chemistry

107

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Template switching during reverse transcription promotes recombination in retroviruses. Efficient switches have been measured in vitro on hairpin-containing RNA templates by a two-step mechanism. Pausing of the reverse transcriptase (RT) at the hairpin base allowed enhanced cleavage of the initial donor RNA template, exposing regions of the cDNA and allowing the acceptor to base pair with the cDNA. This defines the first or docking step. The primer continued synthesis on the donor, transferring or locking in a second step. Here we determine the enzyme-dependent factors that influence template switching by comparing the RTs from human immunodeficiency virus, type 1 (HIV-1), and equine infectious anemia virus (EIAV). HIV-1 RT promoted transfers with higher efficiency than EIAV RT. We found that both RTs paused strongly at the base of the hairpin. While stalled, HIV-1 RT made closely spaced cuts, whereas EIAV RT made only a single cut. Docking occurred efficiently at the multiply cut but not at the singly cut site. HIV-1 nucleocapsid (NC) protein stimulated strand transfers. It improved RNase H activity of both RTs. It allowed the EIAV RT to make a distribution of cuts, greatly stimulating docking at the base of the hairpin. Most likely, it also promoted strand exchange, allowing transfers to be initiated from sites throughout the hairpin. Minor pause sites beyond the base of the hairpin correlated with the locking sites. The strand exchange properties of NC likely promote this step. We present a model that explains the roles of RNase H specificity, template structure, and properties of NC in the two-step transfer reaction.

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Higher Selection Pressure from Antiretroviral Drugs in Vivo Results in Increased Evolutionary Distance in HIV-1 pol

Cited by 29 publications

References 42 publications

The Remarkable Frequency of Human Immunodeficiency Virus Type 1 Genetic Recombination

The Remarkable Frequency of Human Immunodeficiency Virus Type 1 Genetic Recombination

Latent HIV-1 Can Be Reactivated by Cellular Superinfection in a Tat-Dependent Manner, Which Can Lead to the Emergence of Multidrug-Resistant Recombinant Viruses

Role of the Reverse Transcriptase, Nucleocapsid Protein, and Template Structure in the Two-step Transfer Mechanism in Retroviral Recombination

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