Causal relationships between HIV-1 coreceptor utilization, tropism, and pathogenesis in human thymus

The pathogenic differences between CXCR4 (X4)- and CCR5 (R5)-utilizing stra ins of HIV-1 may be predominantly due to differences in viral tropism, whic h in turn may be due to differential coreceptor utilization. We tested this hypothesis in the human thymus organ of the SCID-hu Thy/Liv mouse, using r ecombinants of NL4-3 that were isogenic except for Env coreceptor-binding d eterminants of the V1-V3 loops. Conversion of NL4-3 from an X4 to an R5 iso late was associated with altered tropism for cell subpopulations within the Thy/Liv organ (with a higher frequency of infection of thymic stromal cell s, including macrophages), a slower rate of replication, and a lower level of cytopathicity. These observations underscore the causal relationships be tween tropism, coreceptor use, and cytopathicity in the human thymus in viv o.