Journal of NeuroVirology

, Volume 24, Issue 4, pp 439–453 | Cite as

Ultradeep single-molecule real-time sequencing of HIV envelope reveals complete compartmentalization of highly macrophage-tropic R5 proviral variants in brain and CXCR4-using variants in immune and peripheral tissues

  • Robin L. Brese
  • Maria Paz Gonzalez-Perez
  • Matthew Koch
  • Olivia O’Connell
  • Katherine Luzuriaga
  • Mohan Somasundaran
  • Paul R. Clapham
  • James Jarad Dollar
  • David J Nolan
  • Rebecca RoseEmail author
  • Susanna L. Lamers


Despite combined antiretroviral therapy (cART), HIV+ patients still develop neurological disorders, which may be due to persistent HIV infection and selective evolution in brain tissues. Single-molecule real-time (SMRT) sequencing technology offers an improved opportunity to study the relationship among HIV isolates in the brain and lymphoid tissues because it is capable of generating thousands of long sequence reads in a single run. Here, we used SMRT sequencing to generate ~ 50,000 high-quality full-length HIV envelope sequences (> 2200 bp) from seven autopsy tissues from an HIV+/cART+ subject, including three brain and four non-brain sites. Sanger sequencing was used for comparison with SMRT data and to clone functional pseudoviruses for in vitro tropism assays. Phylogenetic analysis demonstrated that brain-derived HIV was compartmentalized from HIV outside the brain and that the variants from each of the three brain tissues grouped independently. Variants from all peripheral tissues were intermixed on the tree but independent of the brain clades. Due to the large number of sequences, a clustering analysis at three similarity thresholds (99, 99.5, and 99.9%) was also performed. All brain sequences clustered exclusive of any non-brain sequences at all thresholds; however, frontal lobe sequences clustered independently of occipital and parietal lobes. Translated sequences revealed potentially functional differences between brain and non-brain sequences in the location of putative N-linked glycosylation sites (N-sites), V1 length, V3 charge, and the number of V4 N-sites. All brain sequences were predicted to use the CCR5 co-receptor, while most non-brain sequences were predicted to use CXCR4 co-receptor. Tropism results were confirmed by in vitro infection assays. The study is the first to use a SMRT sequencing approach to study HIV compartmentalization in tissues and supports other reports of limited trafficking between brain and non-brain sequences during cART. Due to the long sequence length, we could observe changes along the entire envelope gene, likely caused by differential selective pressure in the brain that may contribute to neurological disease.


Evolution Phylogenetics Clustering Tropism Combined antiretroviral therapy (cART) Next-generation sequencing (NGS) 



We thank Benjamin Murrell (University of California, San Diego) for early discussions on this project. We thank Yvonne Edwards for help in managing PacBio sequencing data at UMASS Med.Sch.

Compliance with ethical standards

Conflict of interest

The authors declare they have no conflict of interest.

Supplementary material

13365_2018_633_MOESM1_ESM.docx (42 kb)
Supplementary Table 1 (DOCX 42 kb)


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Copyright information

© Journal of NeuroVirology, Inc. 2018

Authors and Affiliations

  • Robin L. Brese
    • 1
  • Maria Paz Gonzalez-Perez
    • 1
  • Matthew Koch
    • 1
  • Olivia O’Connell
    • 1
  • Katherine Luzuriaga
    • 1
  • Mohan Somasundaran
    • 1
  • Paul R. Clapham
    • 1
  • James Jarad Dollar
    • 2
  • David J Nolan
    • 2
  • Rebecca Rose
    • 2
    Email author
  • Susanna L. Lamers
    • 2
  1. 1.Program in Molecular MedicineUniversity of Massachusetts Medical SchoolWorcesterUSA
  2. 2.Bioinfoexperts, LLCThibodauxUSA

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