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. 2023 Jan 23;7(2):131-142.
doi: 10.20411/pai.v7i2.524. eCollection 2022.

HIV-1 is Transported into the Central Nervous System by Trafficking Infected Cells

Laura P Kincer  1   2 , Gretja Schnell  3 , Ronald Swanstrom  1   2   3   4 , Melissa B Miller  5 , Serena Spudich  6 , Joseph J Eron  7 , Richard W Price  8 , Sarah B Joseph  1   2   3
Affiliations

HIV-1 is Transported into the Central Nervous System by Trafficking Infected Cells

Laura P Kincer et al. Pathog Immun. .

Abstract

Background: In this work, we carried out a cross-sectional study examining HIV-1 and HCV free virus concentrations in blood and cerebrospinal fluid (CSF) to determine whether HIV-1 enters the central nervous system (CNS) passively as virus particles or in the context of migrating infected cells. If virions migrate freely across the blood-cerebrospinal fluid barrier (BCSFB) or the blood-brain barrier (BBB) then HCV and HIV-1 would be detectable in the CSF at proportions similar to that in the blood. Alternatively, virus entry as an infected cell would favor selective entry of HIV-1.

Methods: We measured HIV-1 and HCV viral loads in the CSF and blood plasma of 4 co-infected participants who were not on antiviral regimens for either infection. We also generated HIV-1 env sequences and performed phylogenetic analyses to determine whether HIV-1 populations in the CSF of these participants were being maintained by local replication.

Results: While CSF samples taken from all participants had detectable levels of HIV-1, HCV was not detectable in any of the CSF samples despite participants having HCV concentrations in their blood plasma, which exceeded that of HIV-1. Further, there was no evidence of compartmentalized HIV-1 replication in the CNS (Supplementary Figure 1). These results are consistent with a model where HIV-1 particles cross the BBB or the BCSFB within infected cells. In this scenario, we would expect HIV-1 to reach the CSF more readily because the blood contains a much greater number of HIV-infected cells than HCV-infected cells.

Conclusions: HCV entry into the CSF is restricted, indicating that virions do not freely migrate across these barriers and supporting the concept that HIV-1 is transported across the BCSFB and/or BBB by the migration of HIV-infected cells as part of an inflammatory response or normal surveillance.

Keywords: CNS; HCV; HIV; NeuroAIDS; blood-brain barrier; blood-cerebrospinal fluid barrier; viral trafficking.

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Conflict of interest statement

UNC is pursuing intellectual property protection for Primer ID. RS is listed as a co-inventor and has received nominal royalties. GS is an employee of Vir Biotechnology Inc. and may hold stock or stock options. Vir Biotechnology provided no funding for this work. The authors have no additional conflicts of interest.

Figures

Figure 1.
Figure 1.
HIV-1 is actively trafficked into the CNS by infected cells. (A) Model of passive diffusion of virus into the CNS. (B) Model of virus trafficking into the CNS in infected cells. (C) HIV-1 has proportionally higher levels of virus in the CSF compared to HCV. The viral loads of HIV-1 and HCV in the blood and CSF are plotted as a ratio of CSF:Blood viral load for each of the 4 participants. Values for HIV-1 are shown in solid circles, for HCV in open circles. Because the HCV viral load was undetectable in the CSF, a value just below the ratio that would have been recorded at the limit of detection (LOD) is shown.
Figure 2.
Figure 2.
HCV is detectable in spiked CSF and PBS. HCV+ blood from 2 participants, 1019 (green triangles) and 1023 (black circles), was used to spike patient matched CSF as well as PBS. Ten percent plasma was mixed with 90% CSF or 90% PBS, and an HCV viral load was performed on these spiked samples along with pure plasma and pure CSF. The limit of detection (LOD) for the HCV VL assay is shown with a dashed line.
See this image and copyright information in PMC

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