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Microglia Exhibit a Unique Intact HIV Reservoir in Human Postmortem Brain Tissue
Marieke M Nühn1, Stephanie B H Gumbs1, Pauline J Schipper1
1Translational Virology, Department of Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
Viruses
|April 26, 2025
Summary
The human immunodeficiency virus (HIV) establishes a persistent reservoir in the brain, primarily within microglia. Intact, replication-competent HIV was found in only one patient, highlighting challenges for HIV cure strategies.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- A persistent human immunodeficiency virus (HIV) proviral reservoir exists within the central nervous system (CNS).
- Understanding the characteristics of this CNS reservoir is crucial for developing effective HIV cure strategies.
- Research has historically focused on cerebrospinal fluid (CSF) due to the difficulty of obtaining brain tissue.
Purpose of the Study:
- To investigate the size, cellular tropism, and infection dynamics of the HIV reservoir in post-mortem human brain tissue.
- To analyze the HIV reservoir across different brain regions in individuals on and off antiretroviral therapy (ART).
- To characterize the replication capacity of HIV in microglia and CD4+ T cells.
Main Methods:
- Analysis of post-mortem brain tissue from five individuals with HIV.
- Isolation of microglia-enriched fractions (CD11b+) from three distinct brain regions.
- Quantification of intact proviral DNA (IPDA) and characterization of full-length envelope reporter viruses.
- Phenotypic analysis of viral clones in CD4+ T cells and monocyte-derived microglia.
Main Results:
- HIV DNA was detected in microglia-enriched fractions from all individuals studied.
- Intact, replication-competent proviruses were identified in only one individual receiving ART, constituting 15% of total proviruses.
- 80% of characterized viral clones replicated efficiently in both microglia and CD4+ T cells, while the remainder were restricted to CD4+ T cells.
- No significant differences in the HIV reservoir were observed across the three brain regions examined.
Conclusions:
- Microglia harbor a distinct HIV brain reservoir in individuals with HIV.
- The presence of intact, replication-competent viruses in microglia suggests their role in viral persistence within the CNS.
- The unique CNS immune environment and microglia characteristics present challenges for HIV eradication strategies.
- The CNS reservoir, particularly within microglia, must be considered in future HIV cure research.
