Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells

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Abstract
Activated CD4 T cells are open to HIV attack, but HIV fails to infect resting cells. New work links this observation to the recently discovered cellular cytidine deaminase APOBEC3G (A3G), an innate antiretroviral that blocks the spread of HIV, if the virus lacks its Vif gene. A3G is now shown to exist in two forms — a large form that is ineffective in preventing cellular infection, and a shorter enzymatically active form that repels the virus. Activated T cells have the long form and are easily infected by HIV, but resting T cells carry the short form so are impervious to HIV infection. Blocking the small form of A3G in resting T cells suddenly makes them susceptible to HIV infection. The discovery suggests new strategies for preventing the spread of HIV infection, either by converting large A3G into the protective smaller form in activated CD4 T-cells, or by preventing the ‘small A3G’ from converting to the large form during T-cell activation. 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 impaired1,2,3. 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.