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Posted: 29 Sep 2011
30 years in 30 weeks, 2002

The HIV protein Vif (virion infectivity factor) got its name for the ability to improve infectivity of HIV in certain cell lines. It’s been long hypothesized that it does so by inhibiting a restriction factor present in some cells, but the eventual discovery of the identity of this factor brought more surprises than expected. APOBEC3G turned out to belong to a whole family of restriction factors that specifically target many different viruses. Their importance is highlighted by the fact that the family of APOBECs, together with TRIM proteins, is separated by some into a whole separate branch of immunity – intrinsic immune system. In their commentary, Drs. Malim and Sheehy describe the discovery of APOBEC3G.

Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein.
Nature. 2002 Aug 8;418(6898):646-50. Epub 2002 Jul 14.
Sheehy AM, Gaddis NC, Choi JD, Malim MH.

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Commentary by Drs. Michael Malim and Ann Sheehy

Dr. Michael Malim
This paper describes the identification of a human gene (now called APOBEC3G) whose protein product naturally exhibits profound anti-HIV-1 activity.  Proteins of this class are known as restriction factors and APOBEC3G was the first such factor found to inhibit HIV-1.  Since that study, and perhaps partially inspired by it, a number of additional human proteins with this general property have been discovered.  This area of HIV-1/AIDS research remains very exciting as scientists continue to decipher more and more unexpected features of the biology of HIV-1, and its interplay with the human host. 

The design of this study built on earlier reports from many groups predicting that the essential viral protein, Vif, acts to overcome a host cell-encoded anti-viral activity.  The molecular explanation for this striking activity had remained elusive for a number of years.  Using a classical genetic approach, comparing the mRNA expression patterns of cells that expressed this activity and cells that did not, we were able to identify a single gene, CEM15 (soon thereafter known as APOBEC3G), that fully accounted for this differential susceptibility to HIV-1 infection. In other words, expression of just this gene in any cell type confers upon that cell the ability to block delta-Vif HIV-1 infection.  This work proved the fundamental hypothesis of the field as correct: without Vif, APOBEC3G effectively prevents HIV-1 from replicating. The research described in this paper was the culmination of at least three years of very patient and hard work, and we still marvel at the fact that one single gene can exert such a potent inhibitory effect on HIV-1. 

Subsequent work on APOBEC3G has been fascinating for many reasons, but perhaps principally because its mechanism of anti-viral action turned out to be unprecedented.  Specifically, APOBEC3G belongs to a group of enzymes known as cytidine deaminases, which have the capacity to change (or mutate) the sequence of bases in DNA or RNA by a process called editing.  Accordingly, the inhibition of HIV-1 infection by APOBEC3G is associated with overwhelming levels of destructive mutation – a consequence of which is viral inactivation through the loss of genetic integrity. 

While we suspected back in 2002 that this work would be of notable significance to virologists, the subsequent elucidation of APOBEC3G’s novel anti-viral mechanism presumably propelled it to a level of far broader interest among biologists – something we certainly had not anticipated at the time. 

Finally, in evaluating our current understanding of this restriction factor, and looking ahead, one significant aspiration of this type of research is that it can be leveraged to develop new approaches for antiviral treatment. 

About the authors:
Michael H. Malim is a Professor at King’s College London, England.
Ann M. Sheehy is an Assistant Professor at the College of the Holy Cross, United States.

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