Analysis of HIV-1 intersubtype recombination breakpoints suggests region with high pairing probability may be a more fundamental factor than sequence similarity affecting HIV-1 recombination.

Lei Jia,Hanping Li,Lin Li,Siyang Liu,Jingyun Li,Jingwan Han,Wei Guo,Tao Gui,Yongjian Liu

doi:10.1186/s12985-016-0616-1

Abstract

BackgroundWith increasing data on HIV-1, a more relevant molecular model describing mechanism details of HIV-1 genetic recombination usually requires upgrades. Currently an incomplete structural understanding of the copy choice mechanism along with several other issues in the field that lack elucidation led us to perform an analysis of the correlation between breakpoint distributions and (1) the probability of base pairing, and (2) intersubtype genetic similarity to further explore structural mechanisms.MethodsNear full length sequences of URFs from Asia, Europe, and Africa (one sequence/patient), and representative sequences of worldwide CRFs were retrieved from the Los Alamos HIV database. Their recombination patterns were analyzed by jpHMM in detail. Then the relationships between breakpoint distributions and (1) the probability of base pairing, and (2) intersubtype genetic similarities were investigated.ResultsPearson correlation test showed that all URF groups and the CRF group exhibit the same breakpoint distribution pattern. Additionally, the Wilcoxon two-sample test indicated a significant and inexplicable limitation of recombination in regions with high pairing probability. These regions have been found to be strongly conserved across distinct biological states (i.e., strong intersubtype similarity), and genetic similarity has been determined to be a very important factor promoting recombination. Thus, the results revealed an unexpected disagreement between intersubtype similarity and breakpoint distribution, which were further confirmed by genetic similarity analysis. Our analysis reveals a critical conflict between results from natural HIV-1 isolates and those from HIV-1-based assay vectors in which genetic similarity has been shown to be a very critical factor promoting recombination.ConclusionsThese results indicate the region with high-pairing probabilities may be a more fundamental factor affecting HIV-1 recombination than sequence similarity in natural HIV-1 infections. Our findings will be relevant in furthering the understanding of HIV-1 recombination mechanisms.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-016-0616-1) contains supplementary material, which is available to authorized users.

Highlights

With increasing data on human immunodeficiency virus type 1 (HIV-1), a more relevant molecular model describing mechanism details of HIV-1 genetic recombination usually requires upgrades
Extensive experiments have been performed on HIV-1 as well as other retroviruses, all suggesting that HIV-1 genetic recombination results from a “copy choice” mechanism i.e. the alternating use of two templates during the synthesis of a single viral DNA strand [3]
The results indicated all the unique recombinant forms (URFs) and circulating recombinant forms (CRFs) groups exhibited the same distribution with similar peaks and valleys (Fig. 1a-d, Table 2)

Summary

Introduction

With increasing data on HIV-1, a more relevant molecular model describing mechanism details of HIV-1 genetic recombination usually requires upgrades. When a host cell is coinfected with two genetically distinct viruses, progeny viral particles with heterodimeric gRNAs would be produced. Upon subsequent infection of a new host cell by these mature heterodimeric progenies, recombination events during reverse transcription would result in a recombinant provirus [1]. Extensive experiments have been performed on HIV-1 as well as other retroviruses, all suggesting that HIV-1 genetic recombination results from a “copy choice” mechanism i.e. the alternating use of two templates during the synthesis of a single viral DNA strand [3]. With an ever increasing amount of data on HIV-1, the proposed genetic recombination mechanism of HIV-1 as well as a more representative molecular model requires repeated upgrades. Donor-acceptor sequence similarity underlies primer strand realignment which is the most critical basis of the model

Methods

Results

Discussion

Conclusion