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Human immunodeficiency virus type 1 T-lymphotropic strains enter macrophages via a CD4- and CXCR4-mediated pathway:
H Schmidtmayerova1, M Alfano, G Nuovo
1The Picower Institute for Medical Research, Manhasset, New York 11030, USA. hsch@picower.edu
Abstract:
The human immunodeficiency virus type 1 (HIV-1) laboratory strains adapted to T-cell lines, as well as most syncytium-inducing primary isolates, replicate poorly in macrophages, which, beside CD4(+) T lymphocytes, are major targets of HIV-1. In the present work, we used a semiquantitative PCR-based technique to study viral entry into cells, kinetics of reverse transcription, and translocation of the viral DNA into the nucleus of macrophages infected with different HIV-1 strains. Our results demonstrate that T-lymphotropic strains efficiently enter macrophages. Entry was inhibited by a monoclonal antibody against CD4 and by stromal cell-derived factor 1alpha, a natural ligand of CXCR4, suggesting that both CD4 and CXCR4 act as receptors on macrophages for HIV-1 T-lymphotropic strains. Analysis of the kinetics of reverse transcription and nuclear import revealed that the most pronounced differences between T-lymphotropic and macrophagetropic strains occurred at the level of nuclear translocation of viral DNA, although a delay in reverse transcription was also observed. These results suggest that postentry steps are critical for restricted replication of T-lymphotropic HIV-1 strains in macrophages.
Insights
T-lymphotropic HIV-1 strains enter macrophages using CD4 and CXCR4 receptors. However, restricted replication in macrophages is due to post-entry steps, specifically nuclear translocation of viral DNA.
Area of Science:
- Virology
- Immunology
Background:
- Macrophages are key targets for Human Immunodeficiency Virus type 1 (HIV-1).
- T-lymphotropic HIV-1 strains exhibit poor replication in macrophages compared to T-lymphocytes.
Purpose of the Study:
- To investigate the mechanisms underlying the restricted replication of T-lymphotropic HIV-1 strains in macrophages.
- To analyze viral entry, reverse transcription, and nuclear translocation in infected macrophages.
Main Methods:
- Utilized a semiquantitative PCR-based technique to assess viral processes.
- Infected macrophages with different HIV-1 strains (T-lymphotropic and macrophagetropic).
- Employed monoclonal antibodies against CD4 and stromal cell-derived factor 1alpha (SDF-1α) to study receptor usage.
Main Results:
- T-lymphotropic HIV-1 strains efficiently enter macrophages, utilizing both CD4 and CXCR4 as receptors.
- Entry inhibition observed with anti-CD4 antibody and SDF-1α, confirming CD4 and CXCR4 roles.
- Post-entry steps, particularly nuclear translocation of viral DNA, showed significant differences between T-lymphotropic and macrophagetropic strains.
- A delay in reverse transcription kinetics was also noted for T-lymphotropic strains.
Conclusions:
- CD4 and CXCR4 are identified as receptors for T-lymphotropic HIV-1 strains on macrophages.
- Post-entry events, especially the nuclear import of viral DNA, are critical determinants of restricted HIV-1 replication in macrophages.
- Understanding these post-entry barriers could inform strategies to enhance HIV-1 control in macrophages.