The effect of HIV-1 infection on S1P-R1 expression and function in thymocytes and their progenitors during entry into and egress from the human thymus

Abstract

Abstract Lack of adequate T cell regeneration in HIV infected individuals is likely due to a defect in the entry of hematopoietic stem cells (HSC) into and egress of naïve T cells from the thymus to the periphery. We studied the effect of HIV-1 infection on the receptors to Sphingosine-1-phosphate (S1P), a chemotactic sphingolipid mediator, during thymocyte trafficking. Our novel findings show that HIV infection changes the expression patterns of S1P-R1 on thymocytes about to exit the thymus. To examine the dynamics of S1P-R1 expression on HSC progenitors and thymocytes during HIV infection, mice implanted with human fetal thymus/liver infected with CXCR4- or CCR5-tropic HIV-1 were injected intravenously with CFSE-labeled HSC. In infected mice CFSE labeled CD34+ progenitors developed into mature thymocytes in the thymic implant and a subset expressed S1P-R1, indicating that entry into the thymus and development are functional during early HIV infection. Surprisingly, we found that S1P-R1 was significantly upregulated in mature thymocytes post-HIV infection. Intriguingly, S1P-R1 was also upregulated by HIV within the CD3+CD69+ population, which normally does not express S1P-R1. S1P-R1 signaling as measured by phosphorylated Akt (pAkt) was not impaired in infected thymocytes, which is interesting in the context of published data demonstrating that S1P-R1 response in HIV infection may be impaired in other cell types. Further results show that the mechanism of increased S1P-R1 in the thymus by HIV may be due to cytokines including Interferon-beta (IFN-β), which significantly increased S1P-R1 expression in both CD3hiCD69- and CD3+CD69+ thymocyte subsets treated in vitro with exogenous cytokine.