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Using gene delivery to protect HIV-susceptible CNS cells: inhibiting HIV replication in microglia
Pierre Cordelier1, David S Strayer
1Department of Pathology, Jefferson Medical College, 1020 Locust Street, Room 251, Philadelphia, PA 19107, USA.
Abstract:
Antiretroviral chemotherapy penetrates the CNS poorly. CNS HIV, thus sheltered, may injure the brain and complicate control of systemic HIV infection. Microglial cells play a major role in HIV persistence in the CNS but are rarely targeted for gene delivery. Because recombinant SV40 vectors (rSV40s) transduce other phagocytic cells efficiently, we tested rSV40 delivery of anti-HIV genetic therapy to microglial cells. Microglia prepared as enriched cultures from human fetal brain, were transduced with marker vectors, SV(RFP) and SV(Nef/FLAG), respectively, carrying DsRed and HIV-1 Nef bearing a FLAG epitope. By immunostaining and FACS, 95% of unselected cells expressed the transgenes, without detectable toxicity. Microglia were transduced with SV(AT), carrying human alpha1-antitrypsin (alpha1AT), which blocks Env and Gag processing. SV(AT)-treated microglia strongly resisted challenge with HIV-1BaL, even when microglia were transduced with SV(AT) following HIV challenge. Thus, rSV40s effectively transduce microglia and protect them from HIV.
Insights
Recombinant SV40 vectors effectively deliver anti-HIV gene therapy to microglial cells, protecting them from infection. This novel approach enhances control of human immunodeficiency virus (HIV) in the central nervous system (CNS).
Area of Science:
- Neuroscience
- Virology
- Gene Therapy
Background:
- Antiretroviral drugs poorly penetrate the central nervous system (CNS), allowing human immunodeficiency virus (HIV) persistence in microglia.
- Microglial cells are crucial for HIV persistence within the CNS and are a potential target for gene therapy.
- Current gene delivery methods rarely target microglial cells effectively.
Purpose of the Study:
- To evaluate the efficacy of recombinant simian virus 40 vectors (rSV40s) for delivering anti-HIV genetic material to human microglial cells.
- To assess the protective effect of rSV40-mediated gene transfer against HIV infection in microglia.
Main Methods:
- Enriched cultures of human fetal microglia were transduced with rSV40 vectors carrying marker genes (DsRed, FLAG-tagged HIV-1 Nef).
- Transduction efficiency and toxicity were assessed using immunostaining and fluorescence-activated cell sorting (FACS).
- Microglia were subsequently transduced with an rSV40 vector encoding alpha1-antitrypsin (alpha1AT) and challenged with HIV-1BaL.
Main Results:
- rSV40 vectors achieved high transduction rates (95%) in microglia without detectable toxicity.
- Microglia treated with SV(AT) demonstrated strong resistance to HIV-1BaL challenge.
- Protection was observed even when microglia were treated post-HIV exposure.
Conclusions:
- rSV40 vectors are effective tools for gene delivery to microglial cells.
- rSV40-mediated delivery of alpha1-antitrypsin confers significant resistance to HIV infection in microglia.
- This strategy holds promise for controlling HIV persistence and injury within the CNS.
