Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells.
In contrast to activated CD4+ T cells, resting human CD4+ T cells circulating in blood are highly resistant to infection with human immunodeficiency virus (HIV). Whether the inability of HIV to infect these resting CD4+ T cells is due to the lack of a key factor, or alternatively reflects the presence of an efficient mechanism for defence against HIV, is not clear. Here we show that the anti-retroviral deoxycytidine deaminase APOBEC3G strongly protects unstimulated peripheral blood CD4+ T cells against HIV-1 infection. In activated CD4+ T cells, cytoplasmic APOBEC3G resides in an enzymatically inactive, high-molecular-mass (HMM) ribonucleoprotein complex that converts to an enzymatically active low-molecular-mass (LMM) form after treatment with RNase. In contrast, LMM APOBEC3G predominates in unstimulated CD4+ T cells, where HIV-1 replication is blocked and reverse transcription is impaired. Mitogen activation induces the recruitment of LMM APOBEC3G into the HMM complex, and this correlates with a sharp increase in permissivity for HIV infection in these stimulated cells. Notably, when APOBEC3G-specific small interfering RNAs are introduced into unstimulated CD4+ T cells, the early replication block encountered by HIV-1 is greatly relieved. Thus, LMM APOBEC3G functions as a potent post-entry restriction factor for HIV-1 in unstimulated CD4+ T cells. Surprisingly, sequencing of the reverse transcripts slowly formed in unstimulated CD4+ T cells reveals only low levels of dG dA hypermutation, raising the possibility that the APOBEC3G-restricting activity may not be strictly dependent on deoxycytidine deamination
Chiu
Ya-Lin
YL
Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94143, USA.
Soros
Vanessa B
VB
Kreisberg
Jason F
JF
Stopak
Kim
K
Yonemoto
Wes
W
Greene
Warner C
WC
D000071480:APOBEC-3G Deaminase; D000595:Amino Acid Sequence; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism / Q000821:virology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003564:Cytidine Deaminase; D003593:Cytoplasm / Q000201:enzymology; D004789:Enzyme Activation; D016346:Gene Products, vif / Q000378:metabolism; D015752:Genes, env / Q000235:genetics; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D008934:Mitogens / Q000494:pharmacology; D008969:Molecular Sequence Data; D008970:Molecular Weight; D046912:Multiprotein Complexes / Q000378:metabolism; D009700:Nucleoside Deaminases; D009928:Organ Specificity; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012097:Repressor Proteins; D012260:Ribonucleases / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology; D054320:vif Gene Products, Human Immunodeficiency Virus
D016346:Gene Products, vif; D008934:Mitogens; D046912:Multiprotein Complexes; D011506:Proteins; D012097:Repressor Proteins; D025801:Ubiquitin; D054320:vif Gene Products, Human Immunodeficiency Virus; D012260:Ribonucleases; D009700:Nucleoside Deaminases; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase