Deep Sequencing Reveals Central Nervous System Compartmentalization in Multiple Transmitted/Founder Virus Acute HIV-1 Infection

Sodsai Tovanabutra, Rujipas Sirijatuphat, Phuc T Pham, Lydia Bonar, Elizabeth A Harbolick, Meera Bose, Hongshuo Song, David Chang, Celina Oropeza, Anne Marie O'Sullivan, Joyce Balinang, Eugene Kroon, Donn J Colby, Carlo Sacdalan, Joanna Hellmuth, Phillip Chan, Peeriya Prueksakaew, Suteeraporn Pinyakorn, Linda L Jagodzinski, Duanghathai Sutthichom, Suwanna Pattamaswin, Mark de Souza, Robert A Gramzinski, Jerome H Kim, Nelson L Michael, Merlin L Robb, Nittaya Phanuphak, Jintanat Ananworanich, Victor Valcour, Gustavo H Kijak, Eric Sanders-Buell, Serena Spudich, MHRP Viral Sequencing Core, RV254/SEARCH 010 Study Team, Sodsai Tovanabutra, Rujipas Sirijatuphat, Phuc T Pham, Lydia Bonar, Elizabeth A Harbolick, Meera Bose, Hongshuo Song, David Chang, Celina Oropeza, Anne Marie O'Sullivan, Joyce Balinang, Eugene Kroon, Donn J Colby, Carlo Sacdalan, Joanna Hellmuth, Phillip Chan, Peeriya Prueksakaew, Suteeraporn Pinyakorn, Linda L Jagodzinski, Duanghathai Sutthichom, Suwanna Pattamaswin, Mark de Souza, Robert A Gramzinski, Jerome H Kim, Nelson L Michael, Merlin L Robb, Nittaya Phanuphak, Jintanat Ananworanich, Victor Valcour, Gustavo H Kijak, Eric Sanders-Buell, Serena Spudich, MHRP Viral Sequencing Core, RV254/SEARCH 010 Study Team

Abstract

HIV-1 disseminates to a broad range of tissue compartments during acute HIV-1 infection (AHI). The central nervous system (CNS) can serve as an early and persistent site of viral replication, which poses a potential challenge for HIV-1 remission strategies that target the HIV reservoir. CNS compartmentalization is a key feature of HIV-1 neuropathogenesis. Thus far, the timing of how early CNS compartmentalization develops after infection is unknown. We examined whether HIV-1 transmitted/founder (T/F) viruses differ between CNS and blood during AHI using single-genome sequencing of envelope gene and further examined subregions in pol and env using next-generation sequencing in paired plasma and cerebrospinal fluid (CSF) from 18 individuals. Different proportions of mostly minor variants were found in six of the eight multiple T/F-infected individuals, indicating enrichment of some variants in CSF that may lead to significant compartmentalization in the later stages of infection. This study provides evidence for the first time that HIV-1 compartmentalization in the CNS can occur within days of HIV-1 exposure in multiple T/F infections. Further understanding of factors that determine enrichment of T/F variants in the CNS, as well as potential long-term implications of these findings for persistence of HIV-1 reservoirs and neurological impairment in HIV, is needed.

Trial registration: ClinicalTrials.gov NCT00796146.

Keywords: HIV-1; acute HIV-1 infection (AHI); central nervous system (CNS); cerebrospinal fluid (CSF); compartmentalization; multiple infections; next-generation sequencing (NGS); single-genome amplification (SGA); transmitted/founder (T/F) virus.

Conflict of interest statement

The authors declare no conflict of interest. G.H.K is currently employed by GSK Vaccines but his participation in this study precedes the current employment.

Figures

Figure 1
Figure 1
Maximum likelihood tree of envelope gp160 gene sequences. Sequences were retrieved from participant plasma (circle symbol) and cerebrospinal fluid (CSF) (triangle symbol). Reference sequences include HXB2 and CM244 (GenBank accession K03455 and AY713425, respectively).
Figure 2
Figure 2
Proportions of plasma and CSF variants from three multiple transmitted/founder (T/F)-infected participants observed by next-generation sequencing platforms: participant 2547279, participant 2546340, and participant 2549813.
Figure 2
Figure 2
Proportions of plasma and CSF variants from three multiple transmitted/founder (T/F)-infected participants observed by next-generation sequencing platforms: participant 2547279, participant 2546340, and participant 2549813.

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