Rebound HIV-1 in cerebrospinal fluid after antiviral therapy interruption is mainly clonally amplified R5 T cell-tropic virus

Laura P Kincer; Sarah Beth Joseph; Maria M Gilleece; Blake M Hauser; Sabrina Sizemore; Shuntai Zhou; Clara Di Germanio; Henrik Zetterberg; Dietmar Fuchs; Steven G Deeks; Serena Spudich; Magnus Gisslen; Richard W Price; Ronald Swanstrom

doi:10.1038/s41564-022-01306-6

Rebound HIV-1 in cerebrospinal fluid after antiviral therapy interruption is mainly clonally amplified R5 T cell-tropic virus

Nat Microbiol. 2023 Feb;8(2):260-271. doi: 10.1038/s41564-022-01306-6. Epub 2023 Jan 30.

Authors

Laura P Kincer^{1

2}, Sarah Beth Joseph^{1

2

3

4}, Maria M Gilleece^{2

5}, Blake M Hauser^{2

6}, Sabrina Sizemore², Shuntai Zhou^{1

2}, Clara Di Germanio^{7

8}, Henrik Zetterberg^{9

10

11

12

13}, Dietmar Fuchs¹⁴, Steven G Deeks¹⁵, Serena Spudich¹⁶, Magnus Gisslen^{17

18}, Richard W Price¹⁹, Ronald Swanstrom^{20

21

22}

Affiliations

¹ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ UNC Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Biogen, Research Triangle Park, NC, USA.
⁶ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
⁷ Vitalant Research Institute, San Francisco, CA, USA.
⁸ Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
⁹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
¹⁰ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹¹ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
¹² UK Dementia Research Institute at UCL, London, UK.
¹³ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
¹⁴ Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
¹⁵ Division of HIV, Infectious Diseases, and Global Medicine, Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, CA, USA.
¹⁶ Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.
¹⁷ Department of Infectious Diseases, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
¹⁸ Region Västra Götaland, Sahlgrenska University Hospital, Department of Infectious Diseases, Gothenburg, Sweden.
¹⁹ Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
²⁰ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. risunc@med.unc.edu.
²¹ UNC Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. risunc@med.unc.edu.
²² Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. risunc@med.unc.edu.

Abstract

HIV-1 persists as a latent reservoir in people receiving suppressive antiretroviral therapy (ART). When ART is interrupted (treatment interruption/TI), rebound virus re-initiates systemic infection in the lymphoid system. During TI, HIV-1 is also detected in cerebrospinal fluid (CSF), although the source of this rebound virus is unknown. To investigate whether there is a distinct HIV-1 reservoir in the central nervous system (CNS), we compared rebound virus after TI in the blood and CSF of 11 participants. Peak rebound CSF viral loads vary and we show that high viral loads and the appearance of clonally amplified viral lineages in the CSF are correlated with the transient influx of white blood cells. We found no evidence of rebound macrophage-tropic virus in the CSF, even in one individual who had macrophage-tropic HIV-1 in the CSF pre-therapy. We propose a model in which R5 T cell-tropic virus is released from infected T cells that enter the CNS from the blood (or are resident in the CNS during therapy), with clonal amplification of infected T cells and virus replication occurring in the CNS during TI.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / therapeutic use
Central Nervous System
HIV Infections* / drug therapy
HIV-1* / genetics
Humans
T-Lymphocytes

Substances

Antiviral Agents

Abstract

Publication types

MeSH terms

Substances

Grants and funding