'Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells'

In activated CD4+ T cells, cytoplasmic APOBEC3G resides in an enzymatically inert, high-molecular-mass isomer that converts to an enzymatically active low-molecular-mass isomer after treatment with RNase. In contrast, LMM APOBEC3G predominates in resting CD4+ T cells, blocking replication and impairing the activity of reverse transcription. Activated CD4+ T cells, however, are readily infected by (HIV). Mitogen activation promotes mobilization of LMM APOBEC3G into the HMM complex, and this correlates with a sharp increase in permissivity for HIV infection in these activated cells (Chiu and Greene, 2009).


'In Vivo versus In Vitro APOBEC'

The situation regarding hypermutation observed in HTLV DNA in vitro is not mirrored in vivo hypermutation. Mahieux et al. (2005) noted extensive hypermutation of HTLV genomes by APOBEC 3 in vitro, but mutated HTLV-1 genomes were not identified in peripheral blood mononuclear cell DNA from ten patients with non-malignant HTLV-1 infection in vivo. Thus, although HTLV-1 DNA can indeed be edited by at least four APOBEC3 cytidine deaminases in vitro, their effects are conspicuously absent in vivo (Kolokithas et al. 2010).


'MLVs evade APOBEC'

MuLV glycogag protects against APOBEC and APOBEC has no affect within mitotic cells. The majority (some 95%) of PBMCs are inactive. Once an MLV gets inside one of these cells they become latent thereafter propagating via clonal expansion. Hence they appear to have evolved to counter the effects of APOBEC both by infecting mitotic cells and stimulating mitotic division of those cells (Kolokithas et al. 2010).

“These results suggest that MLV has evolved specific mechanisms to block the ability of Apobec proteins to mediate deaminase-dependent hypermutation.” (Browne and Littman, 2008).

Human APOBEC3 has less of a mutagenic effect on MuLVs than it does on HIV. APOBEC3G also causes markedly less hypermutation of MLV DNA than of HIV DNA (Browne and Littman, 2008).

Gandhi et al. (2008) reported that many studies show that the APOBEC3 family of cytidine deaminases can inhibit (HIV-1) replication, but the significance of this host defense mechanism does not seem to be important as HIV readily establishes infections in humans.

The authors study is examining hypermutation in vivo and the weight of evidence strongly suggests that it is unsafe to extrapolate such results into in vivo conditions.


'Viral latency can limit hypermutation'

Retroviruses rapidly establish latency in the cells which survive the initial infection to be reawakened by immune or inflammatory stimulation (Abbas and Herbein, 2012). This mechanism coupled with clonal expansion largely mitigates the action of APOBEC in vivo, which is likely the reason why the results of in vivo experiments and in vitro ones regarding the effects of APOBEC are so very different.


'Data restricted by the use of a consensus sequence'

Finally a consensus sequence does not account for genomic variation, which in itself could influence the viruses relationship with APOBEC. Thus a range of chimeric gags need to be used.



'REFERENCES'

Abbas W, Herbein G. 2012. Molecular Understanding of HIV-1 Latency. Advances in Virology. 2012, Article ID 574967, 14 pages

Browne EP, Littman DR. 2008. Species-Specific Restriction of Apobec3-Mediated Hypermutation. J. Virol. 82, 1305-1313

Chiu YL, Greene WC. 2009. APOBEC3G: an intracellular centurion. Philos Trans R Soc Lond B Biol Sci. 364(1517):689-703.

Gandhi SK, Siliciano JD, Bailey J, Siliciano RF, Blankson JN. 2008. Role of APOBEC3G/F-Mediated Hypermutation in the Control of Human Immunodeficiency Virus Type 1 in Elite Suppressors. J Virol. 2008 March; 82(6): 3125–3130.

Kolokithas A, Rosenke K, Malik F, et al. 2010. The Glycosylated Gag Protein of a Murine Leukemia Virus Inhibits the Antiretroviral Function of APOBEC3. J Virol. 84(20): 10933–10936.

Mahieux R, Suspène R, Delebecque F, et al. 2005. Extensive editing of a small fraction of human T-cell leukemia virus type 1 genomes by four APOBEC3 cytidine deaminases. J Gen Virol. 86, 2489-2494