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Published on: September 19, 2010
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.
Abstract:
A proviral reservoir persists within the central nervous system (CNS) of people with HIV, but its characteristics remain poorly understood. Research has primarily focused on cerebrospinal fluid (CSF), as acquiring brain tissue is challenging. We examined size, cellular tropism, and infection-dynamics of the viral reservoir in post-mortem brain tissue from five individuals on and off antiretroviral therapy (ART) across three brain regions. Microglia-enriched fractions (CD11b+) were isolated and levels of intact proviral DNA were quantified (IPDA). Full-length envelope reporter viruses were generated and characterized in CD4+ T cells and monocyte-derived microglia. HIV DNA was observed in microglia-enriched fractions of all individuals, but intact proviruses were identified only in one ART-treated individual, representing 15% of the total proviruses. Phenotypic analyses of clones from this individual showed that 80% replicated efficiently in microglia and CD4+ T cells, while the remaining viruses replicated only in CD4+ T cells. No region-specific effects were observed. These results indicate a distinct HIV brain reservoir in microglia for all individuals, although intact proviruses were detected in only one. Given the unique immune environment of the CNS, the characteristics of microglia, and the challenges associated with targeting these cells, the CNS reservoir should be considered in cure strategies.
Insights
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.
