Distinct patterns of cytokine regulation of APOBEC3G expression and activity in primary lymphocytes, macrophages, and dendritic cells.
Human APOBEC3G (A3G), a deoxycytidine deaminase, is a broadly acting antiretroviral factor expressed in a variety of cells. Mitogen activation of CD4 T cells enhances A3G expression and leads to recruitment of low molecular mass (LMM) A3G, which functions as a post-entry human immunodeficiency virus (HIV) restriction factor, into enzymatically inactive, high molecular mass (HMM) RNA-protein complexes that include Staufen RNA-transporting granules. We now report that interleukin-2 (IL-2), IL-15 and, to a lesser extent, IL-7 enhance the expression of A3G in peripheral blood lymphocytes and that this effect is blocked by inhibitors of the JAK and MAPK signaling pathways. In mixed cultures of CD4+ T cells containing either HMM or LMM A3G, HIV preferentially infected cells containing HMM A3G. A3G shifted into a HMM complex when IL-2, -7, or -15 was added to resting T cells, likely explaining how cytokine treatment renders resting CD4+ T cells permissive to HIV infection. Similarly, poly(I:C)/tumor necrosis factor-alpha-induced maturation of dendritic cells was associated with a sharp increase in A3G expression; however, this induction led to the accumulation of LMM A3G. Together, these results highlight the distinct inductive effects of select cytokines on A3G gene expression and A3G complex assembly that occur in natural cellular targets of HIV infection.
Stopak
Kim S
KS
Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94158, USA.
Chiu
Ya-Lin
YL
Kropp
Jerry
J
Grant
Robert M
RM
Greene
Warner C
WC
D000071480:APOBEC-3G Deaminase; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology; D002460:Cell Line; D003564:Cytidine Deaminase; D016207:Cytokines / Q000502:physiology*; D003713:Dendritic Cells / Q000378:metabolism* / Q000821:virology; D005786:Gene Expression Regulation / Q000276:immunology; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D007372:Interferons / Q000502:physiology; D019409:Interleukin-15 / Q000502:physiology; D007376:Interleukin-2 / Q000502:physiology; D015851:Interleukin-7 / Q000502:physiology; D008264:Macrophages / Q000378:metabolism* / Q000821:virology; D009700:Nucleoside Deaminases / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
D016207:Cytokines; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D012097:Repressor Proteins; D007372:Interferons; D009700:Nucleoside Deaminases; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase