Estimating the in-vivo HIV template switching and recombination rate

Cromer, Deborah; Grimm, Andrew; Schlub, Timothy E.; Mak, Johnson; Davenport, Miles P.

doi:10.1097/qad.0000000000000936

Cited by 22 publications

(19 citation statements)

References 30 publications

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“…This is not surprising given that all sets of sequences used in the simulation had very low within-alignment diversity (the within T/F mean Hamming distance range per nucleotide per sequence was 0.76–2.93% across all parental pairs), and many of the random recombination breakpoints in our simulation occur in sequence stretches where both parents were identical or nearly identical. As a result, this study alone cannot bound the recombination rate from above, and Cromer et al 31 values are consistent with the lower bounds we obtain.…”

Section: Resultssupporting

confidence: 89%

“…Template switches occurring in nearly identical regions of the genome are likely to go undetected. Cromer et al 31 modeled this phenomenon and estimated between 5 and 14 template switches per recombinant genome. In this study, we observed a high frequency of recombination breakpoints in our data when both significant and non-significant but potential breakpoints were considered, consistent with what was reported by Cromer et al 31 .…”

Section: Resultsmentioning

confidence: 99%

“…Cromer et al 31 modeled this phenomenon and estimated between 5 and 14 template switches per recombinant genome. In this study, we observed a high frequency of recombination breakpoints in our data when both significant and non-significant but potential breakpoints were considered, consistent with what was reported by Cromer et al 31 . However, because of regions of near identity between the parents, the significant breakpoint counts of RAPR are inevitably lower than the true number of template switches, as illustrated in Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We used this example to illustrate how to apply RAPR in a single T/F setting and illustrate the role of recombination in carrying forward resistance mutations in a complex quasispecies. While heterogeneous infections have been analyzed before to estimate recombination rates 31 , and longitudinal samples have been used to estimate recombination breakpoints 32 , this is the first study to estimate how both recombination rates and the accumulation of breakpoints contribute to the evolution of the HIV-1 quasispecies over time during natural infection.…”

Section: Introductionmentioning

confidence: 99%

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Tracking HIV-1 recombination to resolve its contribution to HIV-1 evolution in natural infection

et al. 2018

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Recombination in HIV-1 is well documented, but its importance in the low-diversity setting of within-host diversification is less understood. Here we develop a novel computational tool (RAPR (Recombination Analysis PRogram)) to enable a detailed view of in vivo viral recombination during early infection, and we apply it to near-full-length HIV-1 genome sequences from longitudinal samples. Recombinant genomes rapidly replace transmitted/founder (T/F) lineages, with a median half-time of 27 days, increasing the genetic complexity of the viral population. We identify recombination hot and cold spots that differ from those observed in inter-subtype recombinants. Furthermore, RAPR analysis of longitudinal samples from an individual with well-characterized neutralizing antibody responses shows that recombination helps carry forward resistance-conferring mutations in the diversifying quasispecies. These findings provide insight into molecular mechanisms by which viral recombination contributes to HIV-1 persistence and immunopathogenesis and have implications for studies of HIV transmission and evolution in vivo.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tracking HIV-1 recombination to resolve its contribution to HIV-1 evolution in natural infection

et al. 2018

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“…Although recombination has been intensively studied in cell culture and in vitro, it has been difficult to quantify its contribution to viral genetic diversity in vivo due to the difficulty of detecting and tracking the history of individual viruses. Cromer and colleagues tackled this problem using data obtained from single genome amplification at early time points [ 5 ]. Previous studies have shown that just after infection, viral diversity is sufficiently low to reconstruct the genetic makeup of the founder virus [ 6 ].…”

Section: Main Textmentioning

confidence: 99%

A step forward understanding HIV-1 diversity

Smyth

Negroni

2016

Retrovirology

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Human immunodeficiency virus (HIV) populations are characterized by extensive genetic diversity. Antigenic diversification is essential for escape from immune selection and therapy, and remains one of the major obstacles for the development of an efficient vaccine strategy. Even if intensive efforts have been made for understanding the molecular mechanisms responsible for genetic diversity in HIV, conclusive data in vivo is still lacking. Recent works have addressed this issue, focusing on the identification of the sources of genetic diversity during in vivo infections and on the estimate of the pervasiveness of genetic recombination during replication in vivo. Surprisingly, it appears that despite the error-prone nature of the viral polymerase, the bulk of mutations found in patients are indeed due to the effect of a cellular restriction factor. This factor tends to hypermutate the viral genome abolishing viral infectivity. When hypermutation is incomplete, the virus retains infectivity and converts the effect of the cellular factor to its advantage by exploiting it to generate genetic diversity that is beneficial for viral propagation. This view contrasts the long-standing dogma that viral diversity is due to the intrinsic error-prone nature of the viral replication cycle. Besides hypermutations and mutations, recombination is also a pervasive source of genetic diversity. The estimate of the frequency at which this process takes place in vivo has remained elusive, despite extensive efforts in this sense. Now, using single genome amplification, and starting from publically available datasets, it has been obtained a confirmation of the estimates previously made using tissue culture studies. These recent findings are presented here and their implications for the development of future researches are discussed.

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References

2022

Structures and Functions of Retroviral RNAs

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Estimating the in-vivo HIV template switching and recombination rate

Abstract: The in-vivo estimated template switching rate is close to the in-vitro estimated rate found in primary T lymphocytes but not macrophages, which is consistent with the majority of HIV infection occurring in T lymphocytes.

Cited by 22 publications

References 30 publications

Tracking HIV-1 recombination to resolve its contribution to HIV-1 evolution in natural infection

Tracking HIV-1 recombination to resolve its contribution to HIV-1 evolution in natural infection

A step forward understanding HIV-1 diversity

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