1. Gladstone Institute of Virology and Immunology,
2. Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, California 94143, USA

Correspondence to: Warner C. Greene^1,2 Correspondence and requests for materials should be addressed to W.C.G. (Email: wgreene@gladstone.ucsf.edu).

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)^{1, 2, 3, 4}. 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 APOBEC3G⁵ 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^{1, 2, 3}. 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.

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