Abstract
Chronic immune activation and inflammation (e.g., as manifest by production of type I interferons) are major determinants of disease progression in primate lentivirus infections. To investigate the impact of such activation on intrathymic T-cell production, we studied infection of the human thymus implants of SCID-hu Thy/Liv mice with X4 and R5 HIV. X4 HIV was observed to infect CD3−CD4+CD8−CXCR4+CCR5− intrathymic T-cell progenitors (ITTP) and to abrogate thymopoiesis. R5 HIV, by contrast, first established a nonpathogenic infection of thymic macrophages and then, after many weeks, began to replicate in ITTP. We demonstrate here that the tropism of R5 HIV is expanded and pathogenicity enhanced by upregulation of CCR5 on these key T-cell progenitors. Such CCR5 induction was mediated by interferon-α (IFN-α) in both thymic organ cultures and in SCID-hu mice, and antibody neutralization of IFN-α in R5 HIV-infected SCID-hu mice inhibited both CCR5 upregulation and infection of the T-cell progenitors. These observations suggest a mechanism by which IFN-α production may paradoxically expand the tropism of R5 HIV and, in so doing, accelerate disease progression.
Highlights
Human immunodeficiency virus (HIV) disease progression is marked by chronic immune activation associated with accelerated destruction of T cells in the periphery and diminished production of new T cells from progenitors in the thymus and elsewhere [1,2]
The human thymus implants of SCID-hu Thy/Liv mice were inoculated with the X4 HIV clone NL4-3, the R5 HIV isolate BaL, or a chimeric R5 clone of NL4-3 containing the V1-V3 env regions of Ba-L (81A) and monitored for viral replication and thymocyte depletion at 21 and 42 days
Given our previous data showing that infection of intrathymic T-cell progenitors (ITTP) leads to interruption of thymopoiesis [10], these results indicate that IFN-a-induced upregulation of CCR5 on ITTP is likely to result in diminished production of T cells from the thymus
Summary
HIV disease progression is marked by chronic immune activation associated with accelerated destruction of T cells in the periphery and diminished production of new T cells from progenitors in the thymus and elsewhere [1,2]. The detection of X4 HIV as the predominant viral species in peripheral blood is clearly associated with a higher risk of disease progression, about half of patients progress to AIDS in the presence of R5 viruses alone [3,4] or with only the transient appearance of X4 virus [5] Since it is just a small fraction of CD4+ target cells that express the CCR5 coreceptor [6], the mechanisms underlying such intrinsic R5 virus pathogenicity remain unclear. CCR5 is expressed at much lower levels than CXCR4 (,5% versus 30–40% of thymocytes) at all stages of Tcell development in the thymus [6,12,13], and this may explain the decreased pathogenicity of R5 HIV in that organ
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