APOBEC3G-independent reduction in virion infectivity during long-term HIV-1 replication in terminally differentiated macrophages.
APOBEC3G (APO3G) is a cellular cytidine deaminase with potent antiviral activity. In the case of HIV, the antiviral activity of APO3G is counteracted by the viral Vif protein. Monocyte-derived macrophages (MDM) are terminally differentiated, non-dividing cells susceptible to HIV infection. Human MDM are known to express APO3G and HIV replication in these cells is dependent on Vif. Here we analyzed the correlation between HIV-1 replication and APO3G expression in MDM. Replication of wild type HIV-1 induced a gradual 4-5-fold reduction in APO3G expression. The efficiency of APO3G downregulation correlated with the efficiency of virus replication. Interestingly, despite downregulation of APO3G, the relative infectivity of viruses rapidly declined during the course of infection and was already reduced approximately 90% prior to peak virus production. Cell-free virus preparations showed increased levels of a 41 kDa MA-CA processing intermediate. Sequence analysis around the MA-CA cleavage site and the protease and LTR regions did not reveal deaminase-induced hypermutation of the viral genome, suggesting that APO3G activity is not responsible for the incomplete Gag processing. Thus, the loss of infectivity of HIV-1 viruses produced from long-term infected primary macrophages is due to an APO3G-independent mechanism.
Miyagi
Eri
E
Laboratory of Molecular Microbiology, Viral Biochemistry Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0460, USA.
Schwartzkopff
Franziska
F
Plishka
Ronald
R
Buckler-White
Alicia
A
Clouse
Kathleen A
KA
Strebel
Klaus
K
D000071480:APOBEC-3G Deaminase; D001483:Base Sequence; D002454:Cell Differentiation; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D015536:Down-Regulation; D016679:Genome, Viral; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000201:enzymology / Q000473:pathology / Q000821:virology; D009154:Mutation; D011499:Protein Processing, Post-Translational; D014774:Virulence; D014779:Virus Replication / Q000502:physiology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
D017931:DNA Primers; D004279:DNA, Viral; D054301:gag Gene Products, Human Immunodeficiency Virus; D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase