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High resolution spatio-temporal assessment of simian/human immunodeficiency virus (SHIV) evolution reveals a highly dynamic process within the host

Alison F. Feder, Christopher Kline, Patricia Polacino, Mackenzie Cottrell, Angela D. M. Kashuba, Brandon F. Keele, Shiu-Lok Hu, Dmitri A. Petrov, Pleuni S. Pennings, Zandrea Ambrose
doi: https://doi.org/10.1101/097980
Alison F. Feder
1Department of Biology, Stanford University, Stanford, CA
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Christopher Kline
2Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
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Patricia Polacino
3Washington National Primate Research Center, University of Washington, Seattle, WA
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Mackenzie Cottrell
4Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC
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Angela D. M. Kashuba
4Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC
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Brandon F. Keele
5AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD
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Shiu-Lok Hu
3Washington National Primate Research Center, University of Washington, Seattle, WA
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Dmitri A. Petrov
1Department of Biology, Stanford University, Stanford, CA
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Pleuni S. Pennings
6Department of Biology, San Francisco State University, San Francisco, CA
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Zandrea Ambrose
2Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
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Abstract

The process by which drug-resistant HIV-1 arises and spreads spatially within an infected individual is poorly understood. Studies have found variable results relating how HIV-1 in the blood differs from virus sampled in tissues, offering conflicting findings about whether HIV-1 throughout the body is homogeneously distributed. However, most of these studies sample only two compartments and few have data from multiple time points. To directly measure how drug resistance spreads within a host and to assess how spatial structure impacts its emergence, we examined serial sequences from four macaques infected with RT-SHIVmne027, a simian immunodeficiency virus encoding HIV-1 reverse transcriptase (RT), and treated with RT inhibitors. Both viral DNA and RNA (vDNA and vRNA) were isolated from the blood (including plasma and peripheral blood mononuclear cells), lymph nodes, gut, and vagina at a median of four time points and RT was characterized via single-genome sequencing. The resulting sequences reveal a dynamic system in which vRNA rapidly acquires drug resistance concomitantly across compartments through multiple independent mutations. Fast migration results in the same viral genotypes present across compartments, but not so fast as to equilibrate their frequencies through time. The blood and lymph nodes were found to be compartmentalized rarely, while both the blood and lymph node were more frequently different from mucosal tissues. There is some evidence for an increase in compartmentalization after the onset of selective pressure. This study suggests that even oft-sampled blood does not fully capture the viral dynamics in other parts of the body, especially the gut where vRNA turnover was faster than the plasma and vDNA retained fewer wild-type viruses than other sampled compartments. Our findings of transient compartmentalization across multiple tissues may help explain the varied results of previous compartmentalization studies in HIV-1.

Author Summary HIV-1 is difficult to treat because the virus can evolve to become drug-resistant within the body, but we have an incomplete understanding of where drug resistant viruses originate and how they spread within a person. In this study, four macaques were infected with RT-SHIV, a simian immunodeficiency virus with an HIV-1 reverse transcriptase coding region, which can be targeted with standard HIV drugs. We sampled virus from the macaques before, during and after they became resistant to administered drugs and determined the genetic viral sequences in several parts of the body: blood, lymph nodes, gut, and vagina. We found that drug resistance emerged across compartments nearly simultaneously, and drug resistance evolved multiple independent times within each macaque. Although migration of RT-SHIV between compartments is fast, compartments do not have the same distribution of viral genotypes. This is important because although studies typically sample virus from the blood to study how HIV-1 evolution in humans, our study suggests that it is not fully representative of other parts of the body, particularly the gut.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 04, 2017.
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High resolution spatio-temporal assessment of simian/human immunodeficiency virus (SHIV) evolution reveals a highly dynamic process within the host
Alison F. Feder, Christopher Kline, Patricia Polacino, Mackenzie Cottrell, Angela D. M. Kashuba, Brandon F. Keele, Shiu-Lok Hu, Dmitri A. Petrov, Pleuni S. Pennings, Zandrea Ambrose
bioRxiv 097980; doi: https://doi.org/10.1101/097980
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High resolution spatio-temporal assessment of simian/human immunodeficiency virus (SHIV) evolution reveals a highly dynamic process within the host
Alison F. Feder, Christopher Kline, Patricia Polacino, Mackenzie Cottrell, Angela D. M. Kashuba, Brandon F. Keele, Shiu-Lok Hu, Dmitri A. Petrov, Pleuni S. Pennings, Zandrea Ambrose
bioRxiv 097980; doi: https://doi.org/10.1101/097980

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