Double-stranded RNA analog poly(I:C) inhibits human immunodeficiency virus amplification in dendritic cells via type I interferon-mediated activation of APOBEC3G.
Human immunodeficiency virus (HIV) is taken up by and replicates in immature dendritic cells (imDCs), which can then transfer virus to T cells, amplifying the infection. Strategies known to boost DC function were tested for their ability to overcome this exploitation when added after HIV exposure. Poly(I:C), but not single-stranded RNA (ssRNA) or a standard DC maturation cocktail, elicited type I interferon (IFN) and interleukin-12 (IL-12) p70 production and the appearance of unique small (15- to 20-kDa) fragments of APOBEC3G (A3G) and impeded HIV(Bal) replication in imDCs when added up to 60 h after virus exposure. Comparable effects were mediated by recombinant alpha/beta IFN (IFN-alpha/beta). Neutralizing the anti-IFN-alpha/beta receptor reversed poly(I:C)-induced inhibition of HIV replication and blocked the appearance of the small A3G proteins. The poly(I:C)-induced appearance of small A3G proteins was not accompanied by significant differences in A3G mRNA or A3G monomer expression. Small interfering RNA (siRNA) knockdown of A3G could not be used to reverse the poly(I:C)-induced protective effect, since siRNAs nonspecifically activated the DCs, inducing the appearance of the small A3G proteins and inhibiting HIV infection. Notably, the appearance of small A3G proteins coincided with the shift of high-molecular-mass inactive A3G complexes to the low-molecular-mass (LMM) active A3G complexes. The unique immune stimulation by poly(I:C) with its antiviral effects on imDCs marked by the expression of IFN-alpha/beta and active LMM A3G renders poly(I:C) a promising novel strategy to combat early HIV infection in vivo.
Trapp
Susanna
S
HIV and AIDS Program, Center for Biomedical Research, Population Council, New York, New York 10065,USA.
Derby
Nina R
NR
Singer
Rachel
R
Shaw
Andrew
A
Williams
Vennansha G
VG
Turville
Stuart G
SG
Bess
Julian W
JW
Lifson
Jeffrey D
JD
Robbiani
Melissa
M
D000071480:APOBEC-3G Deaminase; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000276:immunology*; D003713:Dendritic Cells / Q000821:virology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007372:Interferons / Q000096:biosynthesis / Q000276:immunology*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology
D019380:Anti-HIV Agents; D018664:Interleukin-12; D007372:Interferons; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase; D011070:Poly I-C