CXCR4 and CCR5 regulation and expression patterns on T- and monocyte-macrophage cell lineages: implications for susceptibility to infection by HIV-1.

Chemokine receptor expression may vary dramatically among cell subsets. Therefore, the stage of differentiation and the lineage of CD4 cells may profoundly affect their susceptibility to infection by human immunodeficiency virus type 1 (HIV-1). However, the mechanisms of coreceptor competition for association with HIV-1 glycoproteins remain unknown. Here, we propose mathematical models that address the interdependence of the concentrations of CD4 and CCR5 for efficient infection by M-tropic HIV-1 as well as additional complications originated by coreceptor competition caused by posttranslational modifications that positively or negatively affect the coreceptor ability to form complexes with CD4 and/or HIV-1 envelope. Furthermore, since CCR5 and CXCR4 expression on human leukocytes designate these cells as HIV-1 potential targets, the expression of the major HIV-1 coreceptors are also dynamically modeled/quantified as function of the stage of cell differentiation. Results show that although coreceptor competition degree has limited influence on R5 strain infectivity, the infectivity of CXCR4-using isolates strongly depends on the CD4 expression, according to the coreceptor competition model proposed in Lee et al. [J. Virol. 74(11) (2000) 5016]. Understanding the role of in vivo alterations in CD4, CCR5 and CXCR4 densities on HIV-1 cell entry may help the development of optimal control strategies for AIDS pathogenesis.