Background: Human immunodeficiency virus type 2 (HIV-2) is often distinguished clinically by lower viral loads, reduced transmissibility, and longer asymptomatic periods than for human immunodeficiency virus type 1 (HIV-1). Differences in the mutation frequencies of HIV-1 and HIV-2 have been hypothesized to contribute to the attenuated progression of HIV-2 observed clinically. Results: To address this hypothesis, we performed Illumina sequencing of multiple amplicons prepared from cells infected with HIV-1 or HIV-2, resulting in ~4.7 million read pairs and the identification of ~200,000 mutations after data processing. We observed that: (1) HIV-2 displayed significantly lower total mutation, substitution, and transition mutation frequencies than that of HIV-1, along with a mutation spectrum markedly less biased toward G-to-A transitions, (2) G-to-A hypermutation consistent with the activity of APOBEC3 proteins was observed for both HIV-1 and HIV-2 despite the presence of Vif, (3) G-to-A hypermutation was significantly higher for HIV-1 than for HIV-2, and (4) HIV-1 and HIV-2 total mutation frequencies were not significantly different in the absence of G-to-A hypermutants. Conclusions: Taken together, these data demonstrate that HIV-2 exhibits a distinct mutational spectrum and a lower mutation frequency relative to HIV-1. However, the observed differences were primarily due to reduced levels of G-to-A hypermutation for HIV-2. These findings suggest that HIV-2 may be less susceptible than HIV-1 to APOBEC3-mediated hypermutation, but that the fidelities of other mutational sources (such as reverse transcriptase) are relatively similar for HIV-1 and HIV-2. Overall, these data imply that differences in replication fidelity are likely not a major contributing factor to the unique clinical features of HIV-2 infection.
Bibliographical noteFunding Information:
This research was supported by NIH Grant R01 GM105876. J. M. O. R. was supported by the Institute for Molecular Virology Training Program (NIH T32 AI83196), a Doctoral Dissertation Fellowship from the University of Minnesota, and an individual fellowship from the NIH (F31 DA035720-01A1). S. R. L. was supported by an Interdisciplinary Doctoral Fellowship as well as a Doctoral Dissertation Fellowship, both from the University of Minnesota. We are grateful to the staff of the University of Minnesota Genomics Center for helpful advice in the design, performance, and analysis of Illumina sequencing experiments. We would like to thank the Minnesota Supercomputing Institute for providing computing, software, and data storage support for this project. We also thank Christine Clouser for critical comments on the manuscript.
© 2015 Rawson et al.
- Viral evolution
- Viral mutagenesis