Is Nef the elusive cause of HIV-associated hematopoietic dysfunction?
Frank Kirchhoff, Guido Silvestri
Frank Kirchhoff, Guido Silvestri
View: Text | PDF
Commentary

Is Nef the elusive cause of HIV-associated hematopoietic dysfunction?

Abstract

HIV-associated hematological abnormalities involve all lineages of blood cells, thus implying that the virus impairs the function of early HSCs. However, the underlying mechanisms of this defect are unknown, particularly since HSCs are largely resistant to HIV-1 infection. In this issue of the JCI, Prost and colleagues show that the viral accessory protein Negative factor (Nef) plays a potentially critical role in the pathogenesis of HIV/SIV-associated hematopoietic dysfunction by affecting the clonogenic potential of HSCs (see the related article beginning on page 1765). Soluble Nef induces PPARĪ³ in uninfected HSCs, thereby suppressing the expression of STAT5A and STAT5B, two factors necessary for proper HSC function. The identification of this novel activity of extracellular Nef defines a new mechanism of HIV/SIV pathogenesis and suggests that approaches aimed at increasing STAT5A and STAT5B expression may be considered in HIV-infected individuals with prominent hematological abnormalities. The results also raise the question of whether dysregulation of hematopoiesis by extracellular Nef plays a role in the development of T cell immunodeficiency and the high levels of chronic immune activation associated with AIDS.

Authors

Frank Kirchhoff, Guido Silvestri

×

Figure 1

Pathogenesis of the hematological abnormalities associated with HIV infection.

Options: View larger image (or click on image) Download as PowerPoint
Pathogenesis of the hematological abnormalities associated with HIV infe...
(A) Schematic demonstrating how bone marrow–derived HSCs develop into precursors of the three main blood cell lineages (erythroid cells, myeloid cells, and platelets) as well as into the T cell precursors that will mature in the thymus and create the pool of circulating naive and memory CD4+ T cells. Ag, antigen. (B) Schematic demonstrating how the soluble viral accessory protein Nef may affect the ability of HSCs to maintain normal levels of peripheral blood cells, based on the new findings of Prost and coworkers reported in this issue of the JCI (14). In addition, Nef may decrease the production of T cell precursors, thus contributing to the peripheral CD4+ T cell depletion observed in HIV-infected individuals that is caused by both the direct effects of HIV on infected cells and the indirect effects of chronic immune activation.