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Effect of 3'-azido-3'-deoxythymidine on human immunodeficiency virus type 1 replication in human fetal brain
R Geleziunas1, E J Arts, F Boulerice
1McGill AIDS Centre, Lady Davis Institute--Jewish General Hospital, Montreal, Quebec, Canada.
Insights
Human immunodeficiency virus type 1 (HIV-1) replicates in fetal brain macrophages, but nucleoside analogs like AZT effectively block viral replication and progeny production in these cells.
Area of Science:
- Neurovirology
- Cellular Biology
- Antiviral Research
Background:
- Human immunodeficiency virus type 1 (HIV-1) can infect various cell types.
- The central nervous system is a potential site for HIV-1 replication.
- Understanding HIV-1 replication in brain cells is crucial for developing effective treatments.
Purpose of the Study:
- To determine if fetal central nervous system cells support HIV-1 replication.
- To investigate the efficacy of nucleoside analogs in inhibiting HIV-1 replication in brain cells.
- To elucidate the mechanism by which nucleoside analogs affect viral replication in these cells.
Main Methods:
- Fractionation of human fetal brain tissue into astrocyte and macrophage populations.
- Infection of cell populations with an HIV-1 isolate (UHC-1).
- Treatment with nucleoside analogs 3'-azido-3'-deoxythymidine (AZT) and 2'-deoxy-3'-thiacytidine before and after infection.
- Quantification of viral replication, progeny virus production, proviral DNA, and viral transcripts.
Main Results:
- Fetal brain macrophages, but not astrocytes, supported productive UHC-1 replication.
- Pretreatment with AZT or 2'-deoxy-3'-thiacytidine efficiently blocked progeny virus production.
- AZT inhibited the generation of unintegrated proviral DNA and HIV-1 transcripts.
- Late administration of AZT reduced viral levels but did not eliminate unintegrated DNA.
Conclusions:
- Primary cultures of fetal brain macrophages support HIV-1 replication.
- Nucleoside analogs, including AZT, can effectively inhibit HIV-1 replication in fetal brain macrophages.
- AZT may interfere with the accumulation of unintegrated HIV-1 DNA in brain macrophages.
- This study demonstrates the potential of nucleoside analogs to block HIV-1 replication in primary brain cells.
Abstract:
We investigated whether cells derived from the fetal central nervous system can support productive infection by a human immunodeficiency virus type 1 (HIV-1) isolate termed UHC-1, produced by a cellular clone derived from HIV-1 strain HIV-IIIB chronically infected U-937 promonocytic cells, and what the effect of nucleoside analogs might be on viral replication in this system. Fractionation of human fetal brain tissue into two different populations, enriched for either astrocytes or macrophages, showed that only the latter were able to support productive UHC-1 replication and generation of detectable progeny virus. Pretreatment of fetal brain macrophages with either of two nucleoside analogs, 3'-azido-3'-deoxythymidine (AZT) or the (-) enantiomer of 2'-deoxy-3'-thiacytidine, efficiently blocked production of progeny virus. Generation of unintegrated proviral DNA and HIV-1 transcripts were inhibited by pretreatment of fetal brain macrophages with 1 microM AZT. Administration of AZT at 24 h postinfection led to a slight reduction in viral transcript levels and viral progeny production by day 15 postinfection; however, brain macrophages under these conditions did not contain detectable amounts of unintegrated viral DNA. These results suggest that AZT may interfere with the accumulation of unintegrated HIV-1 DNA in brain macrophages. This is the first demonstration that nucleoside analogs are able to block HIV-1 replication in primary cultures of brain cells.