Possible involvement of cell fusion and viral recombination in generation of human immunodeficiency virus variants that display dual resistance to AZT and 3TC

Gu, Zhengxian; Gao, Qing; Faust, Emmanuel A.; Wainberg, Mark A.

doi:10.1099/0022-1317-76-10-2601

Cited by 57 publications

(53 citation statements)

References 23 publications

(20 reference statements)

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“…Although frequent recombination has been observed in most retroviruses (6,15,23,24,26,29,30,(46)(47)(48), many aspects of this phenomenon are still unclear. In this report, we tested whether the rate of recombination could be altered and determined the nature of this potential alteration.…”

Section: Discussionmentioning

confidence: 99%

“…During reverse transcription, both copackaged RNAs can be used as templates to produce a recombinant with a mixture of genetic information from each of the parental RNAs (8,18). Retroviruses recombine at high rates (6,15,23,24,26,29,30,(46)(47)(48). Using murine leukemia virus (MLV)-based vectors with markers separated by 1.0, 1.9, and 7.1 kb, recombination rates of 4.7, 7.4, and 8.2%, respectively, were observed in one round of viral replication (2).…”

mentioning

confidence: 99%

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Effect of the Murine Leukemia Virus Extended Packaging Signal on the Rates and Locations of Retroviral Recombination

Anderson¹,

Pathak

2000

J Virol

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Reverse transcriptase (RT) switches templates frequently during DNA synthesis; the acceptor template can be the same RNA (intramolecular) or the copackaged RNA (intermolecular). Previous results indicated that intramolecular template switching occurred far more frequently than intermolecular template switching. We hypothesized that intermolecular template-switching events (recombination) occurred at a lower efficiency because the copackaged RNA was not accessible to the RT. To test our hypothesis, the murine leukemia virus (MLV) extended packaging signal (⌿ ؉ ) containing a dimer linkage structure (DLS) was relocated from the 5 untranslated region (UTR) to between selectable markers, allowing the two viral RNAs to interact closely in this region. It was found that the overall maximum recombination rates of vectors with ⌿ ؉ in the 5 UTR or ⌿ ؉ between selectable markers were not drastically different. However, vectors with ⌿ ؉ located between selectable markers reached a plateau of recombination rate at a shorter distance. This suggested a limited enhancement of recombination by ⌿ ؉ . The locations of the recombination events were also examined by using restriction enzyme markers. Recombination occurred in all four regions between the selectable markers; the region containing 5 ⌿ ؉ including DLS did not undergo more recombination than expected from the size of the region. These experiments indicated that although the accessibility of the copackaged RNA was important in recombination, other factors existed to limit the number of viruses that were capable of undergoing intermolecular template switching. In addition, recombinants with multiple template switches were observed at a frequency much higher than expected, indicating the presence of high negative interference in the MLV-based system. This extends our observation with the spleen necrosis virus system and suggests that high negative interference may be a common phenomenon in retroviral recombination.Retroviruses package two copies of viral RNA into each virion (9, 28). During reverse transcription, both copackaged RNAs can be used as templates to produce a recombinant with a mixture of genetic information from each of the parental RNAs (8,18). Retroviruses recombine at high rates (6,15,23,24,26,29,30,(46)(47)(48). Using murine leukemia virus (MLV)-based vectors with markers separated by 1.0, 1.9, and 7.1 kb, recombination rates of 4.7, 7.4, and 8.2%, respectively, were observed in one round of viral replication (2).During reverse transcription of the viral genome, the virusencoded enzyme reverse transcriptase (RT) has to perform two template-switching events (named minus-and plus-strand DNA transfer) to complete the synthesis of viral DNA (12). It has been hypothesized that RT is evolutionarily selected to have a low affinity to the template and low processivity in order to complete the two obligatory template-switching events (44). A consequence of this low processivity is that RT may also perform other nonobligatory template-switching events during reverse...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Effect of the Murine Leukemia Virus Extended Packaging Signal on the Rates and Locations of Retroviral Recombination

Anderson¹,

Pathak

2000

J Virol

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“…For example, many of the currently circulating primary strains of HIV-1 are actually intersubtype recombinants (32,33). Additionally, it has been shown that multidrug-resistant virus strains can be generated by recombining the genomes of two viruses, each resistant to a single drug (34). The frequency of recombination in an infected individual can be affected by several factors: the number of doubly infected cells, the efficiency of heterozygote formation, and the rate of template switching during reverse transcription.…”

Section: Reconciling the Paradox Between Single-hit Kinetics Of Virusmentioning

confidence: 99%

Nonrandom HIV-1 infection and double infection via direct and cell-mediated pathways

Dang

Chen

Unutmaz

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

113

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Cells infected with two related retroviruses can generate heterozygous virions, which are the precursors of recombinant proviruses. Although many studies have focused on the frequencies and mechanisms of retroviral recombination, little is known about the dynamics of double infection. To examine this issue, viruses generated from two HIV-1 vectors containing different markers were mixed together, and were used to infect target cells. The numbers of cells expressing none, one, or both markers were measured and were used to calculate whether double infection occurred at frequencies expected from random infection events. We found that double infection occurred significantly more frequently than predicted from random distribution; increased rates of double infection were observed in both a T cell line and primary activated CD4 ؉ T cells. In addition to direct virus infection, we also examined the nature of cell-mediated HIV-1 double infection. Increased double infection was observed in all experiments regardless of whether a cell line or primary human dendritic cells were used for capture and transmission of HIV-1. Therefore, our results indicate that HIV-1 double infection occurs more frequently than it would at random in both direct and cell-mediated HIV-1 infections. To our knowledge, this is the first direct evidence of nonrandom double infection in HIV-1. Frequent double HIV-1 infections in infected individuals would allow the generation of recombinant viruses that could then affect their pathogenesis and evolution.

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“…cessation of therapy or changing immune status) might re-infect the peripheral blood; re-emergence of sensitive genotypes, in plasma following cessation of therapy, has been reported (Albert et al, 1992). The co-existence of such diverse populations within these tissues might also provide ideal conditions for recombination events as have recently been shown to occur in vitro between viruses exhibiting resistance to different antiretrovirals (Gu et al, 1995).…”

Section: Evolution Of the Env And Pol Genesmentioning

confidence: 99%

Concurrent evolution of regions of the envelope and polymerase genes of human immunodeficiency virus type 1 observed during zidovudine (AZT) therapy

Sheehy

Desselberger²,

Whitwell³

et al. 1996

Journal of General Virology

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Nucleotide sequences of regions of the envelope (env) and polymerase (po/) genes of human immunodeficiency virus type 1 (HIV-1) proviral DNA were obtained from sequential blood and autopsy samples from an AIDS patient who had been treated with zidovudine for 9 months, Phylogenetic analyses showed that a reduction in genetic heterogeneity of the env regions of viruses present in the proviral blood population occurred during therapy, and this coincided with an increased pol gene heterogeneity. Differences were observed in different organs obtained post mortem for both the env and pol coding regions. The cardiac blood proviral population consisted mainly of variants which possessed sequences containing mutations at position 215 of the pol gene, associated with drug resistance. By contrast, the brain population consisted entirely of zidovudine sensitive genotypes, and this organ also harboured variants with genetically distinct env sequences. The lymph tissues obtained after death held more diverse proviral env and pol populations, containing both zidovudine sensitive and resistant genotypes.

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Possible involvement of cell fusion and viral recombination in generation of human immunodeficiency virus variants that display dual resistance to AZT and 3TC

Cited by 57 publications

References 23 publications

Effect of the Murine Leukemia Virus Extended Packaging Signal on the Rates and Locations of Retroviral Recombination

Effect of the Murine Leukemia Virus Extended Packaging Signal on the Rates and Locations of Retroviral Recombination

Nonrandom HIV-1 infection and double infection via direct and cell-mediated pathways

Concurrent evolution of regions of the envelope and polymerase genes of human immunodeficiency virus type 1 observed during zidovudine (AZT) therapy

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