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Genotypic Inference of HIV-1 Tropism Using Population-based Sequencing of V3
Published on: December 27, 2010
Causal relationships between HIV-1 coreceptor utilization, tropism, and pathogenesis in human thymus
R D Berkowitz1, S Alexander, J M McCune
1Gladstone Institute of Virology and Immunology, University of California, San Francisco 94141, USA.
AIDS Research and Human Retroviruses
|August 10, 2000
Summary
Differences in HIV-1 coreceptor use (CXCR4 vs CCR5) alter viral tropism and pathogenicity in the human thymus. This study demonstrates how specific viral env gene changes impact infection patterns and disease severity in vivo.
Area of Science:
- Virology
- Immunology
- Pathogenesis
Background:
- Human immunodeficiency virus type 1 (HIV-1) strains utilize different coreceptors, primarily CXCR4 (X4) or CCR5 (R5), influencing disease progression.
- Differences in viral tropism, dictated by coreceptor utilization, are hypothesized to underlie the pathogenic distinctions between X4 and R5 HIV-1 strains.
Purpose of the Study:
- To investigate the causal relationship between HIV-1 coreceptor utilization (X4 vs. R5), viral tropism, and cytopathicity within the human thymus in vivo.
- To determine if altering coreceptor tropism of an HIV-1 strain affects its replication rate and pathogenicity in a humanized mouse model.
Main Methods:
- Utilized the SCID-hu Thy/Liv mouse model, engrafted with human thymus tissue, to study HIV-1 infection in vivo.
- Generated isogenic NL4-3 recombinants differing only in Env V1-V3 loop determinants for coreceptor binding, allowing conversion from X4 to R5 tropism.
- Assessed viral tropism for specific thymic cell subpopulations, replication kinetics, and cytopathicity.
Main Results:
- Conversion of NL4-3 from X4 to R5 tropism resulted in altered tropism within the human thymus, with increased infection of thymic stromal cells and macrophages.
- R5-utilizing variants exhibited a slower replication rate and lower cytopathicity compared to the parental X4 strain.
- These findings confirm differential tropism and pathogenicity associated with coreceptor usage in the human thymus.
Conclusions:
- Coreceptor utilization (CCR5 vs. CXCR4) directly influences HIV-1 tropism and pathogenicity within the human thymus.
- Altering coreceptor tropism impacts the frequency of infection in specific thymic cell types, replication kinetics, and the degree of cellular damage.
- The study establishes a direct link between viral tropism, coreceptor use, and cytopathicity in the context of HIV-1 infection in the human thymus.
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