The Remarkable Frequency of Human Immunodeficiency Virus Type 1 Genetic Recombination

Onafuwa-Nuga, Adewunmi; Telesnitsky, Alice

doi:10.1128/mmbr.00012-09

Cited by 147 publications

(174 citation statements)

References 358 publications

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“…These features include secondary RNA structures and RNA breakage. 5 Recombinants between viruses with different DIS sequences have been identified in human populations; this suggests that other regions of the viral genome can contribute to dimer formation and recombination rate. 7,16 Protein cofactors such as the nucleocapsid protein can also facilitate and stabilize RNA dimerization 4 and thus have an effect on the recombination rate during virus replication.…”

Section: Figmentioning

confidence: 99%

“…HIV-1 recombination results from reverse transcriptase template switching between the two dimerized viral RNAs. 4,5 We recently conducted a longitudinal study in which we analyzed three genetic loci (the C1C2 region of env, RT region of pol, and vvv accessory gene region) of HIV-1 in superinfected subjects. 6 No recombinants or recombination breakpoints were detected in the sequences analyzed of the subtype-discordant infecting strains.…”

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confidence: 99%

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Sequence Analysis of the Dimerization Initiation Site of Concordant and Discordant Viral Variants Superinfecting HIV Type 1 Patients

Mayr

Powell

Kinge

et al. 2011

AIDS Research and Human Retroviruses

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For HIV recombination to occur, the RNAs from two infecting strains within a cell must dimerize at the dimerization initiation site (DIS). We examined the sequence identity at the DIS (697-731 bp, Hxb2 numbering engine) in patients superinfected with concordant HIV-1 strains and compared them to those with discordant strains. Viral RNA in sequential plasma from four subjects superinfected with subtype-discordant and two subjects superinfected with subtype-concordant HIV-1 strains was extracted, amplified (5¢ LTR-early gag: 526-1200 bp, Hxb2 numbering engine), sequenced, and analyzed to determine their compatibility for dimerization in vivo. The concordant viruses infecting the two subjects exhibited identical sequences in the 35-bp-long DIS region while sequences from the discordant viruses revealed single nucleotide changes that were located in the DIS loop (715 bp), its flanking nucleotides (710 bp and 717 bp), and the DIS stem (719 bp). Evidence from in vitro experiments demonstrates that these in vivo changes identified can abolish dimerization and reduce recombination frequency. Therefore, these results revealing differences in the DIS of discordant strains versus the similarity noted for the concordant strains may contribute to the differences in the frequency of recombination in patients superinfected with such HIV-1 variants.T he HIV-1 pandemic is composed of a wide array of genetically diverse strains including innumerable recombinant forms.1 This broad genetic diversity is in part generated by superinfection of one cell by two or more genetically discordant viruses, whose genomes recombine during reverse transcription, producing new mosaic virus strains that can then spread in the population.2,3 For recombination to happen, the RNA genomes of superinfecting viruses have to dimerize at the dimerization initiation site (DIS), a 35-nucleotide sequence that is located in the 5¢ untranslated region of HIV-1 (697-731 bp, Hxb2 numbering engine). The DIS of each viral RNA folds into a hairpin structure that then interact, forming a loop-loop kissing dimer. HIV-1 recombination results from reverse transcriptase template switching between the two dimerized viral RNAs. 4,5 We recently conducted a longitudinal study in which we analyzed three genetic loci (the C1C2 region of env, RT region of pol, and vvv accessory gene region) of HIV-1 in superinfected subjects. 6 No recombinants or recombination breakpoints were detected in the sequences analyzed of the subtype-discordant infecting strains. On the contrary, several recombinants with characteristic breakpoints were detected in subjects superinfected with subtypeconcordant strains.

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Section: Figmentioning

confidence: 99%

mentioning

confidence: 99%

Sequence Analysis of the Dimerization Initiation Site of Concordant and Discordant Viral Variants Superinfecting HIV Type 1 Patients

Mayr

Powell

Kinge

et al. 2011

AIDS Research and Human Retroviruses

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“…These RNAs serve as the viral genome (gRNA) and are used as templates for reverse transcription during an early stage of the replication cycle. gRNAs are selected for packaging as dimers (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), enabling strand-transfermediated recombination during reverse transcription and facilitating genetic evolution under environmental and chemotherapeutic pressures (23).…”

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confidence: 99%

Transcriptional start site heterogeneity modulates the structure and function of the HIV-1 genome

Kharytonchyk

Monti

Smaldino

et al. 2016

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

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119

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The promoter in HIV type 1 (HIV-1) proviral DNA contains three sequential guanosines at the U3-R boundary that have been proposed to function as sites for transcription initiation. Here we show that all three sites are used in cells infected with HIV-1 and that viral RNAs containing a single 5′ capped guanosine ( Cap 1G) are specifically selected for packaging in virions, consistent with a recent report [Masuda et al. (2015) Sci Rep 5:17680]. In addition, we now show that transcripts that begin with two or three capped guanosines ( Cap 2G or Cap 3G) are enriched on polysomes, indicating that RNAs synthesized from different transcription start sites have different functions in viral replication. Because genomes are selected for packaging as dimers, we examined the in vitro monomer-dimer equilibrium properties of Cap 1G, Cap 2G, and Cap 3G 5′-leader RNAs in the NL4-3 strain of HIV-1. Strikingly, under physiological-like ionic conditions in which the Cap 1G 5′-leader RNA adopts a dimeric structure, the Cap 2G and Cap 3G 5′-leader RNAs exist predominantly as monomers. Mutagenesis studies designed to probe for base-pairing interactions suggest that the additional guanosines of the 2G and 3G RNAs remodel the base of the PolyA hairpin, resulting in enhanced sequestration of dimerpromoting residues and stabilization of the monomer. Our studies suggest a mechanism through which the structure, function, and fate of the viral genome can be modulated by the transcriptionally controlled presence or absence of a single 5′ guanosine.HIV-1 | 5′-leader | transcription | RNA | structure

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“…The evolution of the drug resistance is due to the selection pressure rendered by the drugs [105]. The recombination occurs in order to gain the survival advantage and the resistant strains recombine to form the Circulating Recombinant Forms that challenges the established regimens of antiretroviral therapy [106].…”

Section: Antiretroviral Therapymentioning

confidence: 99%

Conventional Vaccine to Prevent AIDS A Paradigm or A Paradox? A SWOT Analysis

Christdas¹

2016

HIV Curr Res

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AIDS as a disease afflicts mankind for more than 3 decades. HIV, the causative is not yet checked with a prophylactic vaccine. The plausibility of the prevention by conventional prophylactic strategies based on Jenner's conventional method of inducing memory response is reviewed here. In order to find the right direction towards achieving this goal, a SWOT analysis is represented here with a Venn diagram. Our increasing awareness on the viral genome and the antiviral treatment with the sensitive diagnostic tools strengthen the efforts, while the viral nature privileges its replenishment by hampering the host immune memory. Though antiviral drugs promise a notable degree of control, they render selection pressure favoring viral escapism with perking quasispecies or circulating recombinant forms (CRF). Few historical clinical trials teach us to frame new opportunities for the conduct of such trials that assures safety. The knowledge has exponentially increased on the host immune response, human genetics, retrovirology, drug development, gene delivery system to understand that HIV is the only pathogen that had the greatest consumption of our time and resources. The technological advancements add to our strength. However, the virus with its biological features proves its intrinsic competency for survival. Though the antiviral therapy confers some hope, the resistant forms pose a threat to their continuation. It emphasizes the need for prevention and suggests novel, unconventional prophylaxis. Treatment as a means of prevention and the use of immunomodulators to decrease the disease progression can help us to win the belligerence against AIDS.

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The Remarkable Frequency of Human Immunodeficiency Virus Type 1 Genetic Recombination

Cited by 147 publications

References 358 publications

Sequence Analysis of the Dimerization Initiation Site of Concordant and Discordant Viral Variants Superinfecting HIV Type 1 Patients

Sequence Analysis of the Dimerization Initiation Site of Concordant and Discordant Viral Variants Superinfecting HIV Type 1 Patients

Transcriptional start site heterogeneity modulates the structure and function of the HIV-1 genome

Conventional Vaccine to Prevent AIDS A Paradigm or A Paradox? A SWOT Analysis

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