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HIV-1 transcriptional regulation in the central nervous system and implications for HIV cure research

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Abstract

Human immunodeficiency virus type-1 (HIV-1) invades the central nervous system (CNS) during acute infection which can result in HIV-associated neurocognitive disorders in up to 50 % of patients, even in the presence of combination antiretroviral therapy (cART). Within the CNS, productive HIV-1 infection occurs in the perivascular macrophages and microglia. Astrocytes also become infected, although their infection is restricted and does not give rise to new viral particles. The major barrier to the elimination of HIV-1 is the establishment of viral reservoirs in different anatomical sites throughout the body and viral persistence during long-term treatment with cART. While the predominant viral reservoir is believed to be resting CD4+ T cells in the blood, other anatomical compartments including the CNS, gut-associated lymphoid tissue, bone marrow, and genital tract can also harbour persistently infected cellular reservoirs of HIV-1. Viral latency is predominantly responsible for HIV-1 persistence and is most likely governed at the transcriptional level. Current clinical trials are testing transcriptional activators, in the background of cART, in an attempt to purge these viral reservoirs and reverse viral latency. These strategies aim to activate viral transcription in cells constituting the viral reservoir, so they can be recognised and cleared by the immune system, while new rounds of infection are blocked by co-administration of cART. The CNS has several unique characteristics that may result in differences in viral transcription and in the way latency is established. These include CNS-specific cell types, different transcription factors, altered immune surveillance, and reduced antiretroviral drug bioavailability. A comprehensive understanding of viral transcription and latency in the CNS is required in order to determine treatment outcomes when using transcriptional activators within the CNS.

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Acknowledgments

This study was supported, in part, from project grants from the Australian National Health and Medical Research Council (NHMRC) (APP1051093) and from the National Institutes of Health (NIH) (R21 MH100594) to MJC and PRG. LRG was supported by a NHMRC Early Career Fellowship (GNT0606967). PRG is the recipient of an Australian Research Council Future Fellowship (FT120100389). The authors gratefully acknowledge the contribution to this work of the Victorian Operational Infrastructure Support Program received by the Burnet Institute.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Center for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, 3004, Victoria, Australia

    Melissa J. Churchill, Steve L. Wesselingh, Paul R. Gorry & Lachlan R. Gray

  2. Department of Microbiology, Monash University, Clayton, Victoria, Australia

    Melissa J. Churchill

  3. Department of Medicine, Monash University, Melbourne, Victoria, Australia

    Melissa J. Churchill

  4. Murdoch Childrens Research Institute, Melbourne, Victoria, Australia

    Daniel J. Cowley

  5. South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia

    Steve L. Wesselingh

  6. Department of Infectious Diseases, Monash University, Melbourne, Victoria, Australia

    Paul R. Gorry & Lachlan R. Gray

  7. Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia

    Paul R. Gorry

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  1. Melissa J. Churchill
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  2. Daniel J. Cowley
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  3. Steve L. Wesselingh
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  4. Paul R. Gorry
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  5. Lachlan R. Gray
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Correspondence to Melissa J. Churchill.

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Churchill, M.J., Cowley, D.J., Wesselingh, S.L. et al. HIV-1 transcriptional regulation in the central nervous system and implications for HIV cure research. J. Neurovirol. 21, 290–300 (2015). https://doi.org/10.1007/s13365-014-0271-5

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  • DOI: https://doi.org/10.1007/s13365-014-0271-5

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