HIV restriction factor blocks respiratory viruses - but not how we thought

Measles virus - is it targeted by an HIV restriction factor?

Cellular organisms have evolved multiple defences to keep viruses and other genetic parasites at bay. One such shield is the development of an advanced adaptive immune system seen in vertebrates while another is the more evolutionary widespread 'innate' system made up of various expressed proteins and small RNAs. These molecules prevent particular stages of the viral replication cycle like entry, replication or exit. 

Another mechanism is to mutate the virus out of existence, i.e. change nucleotides throughout the viral genome so much so as to effectively knock-out that protein's function during infection and slow down replication so much so to allow your bodies' other defences to clear it. Since 2002 we have had tantalising clues that this is functioning during a viral infection, particular HIV and other retroviruses:

Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein.

Reports soon followed showing the mechanism of how this gene protects against these viruses; it was able to induce a large number of guanine to adenine mutations in newly HIV genome DNA copies hereby preventing the incoming genomes from working properly. Importantly, this 'hypermutation' could also contribute to the rapid nature of retroviral evolution when it failed to knockout important viral genes and allowed replication to continue. But of course, HIV encodes a gene - ViF - that counteracts the activity of APOBEC3G largely by directing its intracellular degradation.

APOBEC3G versus HIV Vif protein. This protein degrades the HIV-blocker APOBEC3G. Loss of Vif protein allows this antiviral protein to inhibit HIV infectivity through mutating it's genome. But does this happen during other non-retroviral infections? (http://dailymonthly.com/images/AIDS/Vif.gif)

This was soon extended to another virus: hepatitis B virus. Last month a paper was published (behind pay-wall sadly) documenting this same gene, APOBEC3G inhibition in vitro of a number of respiratory viruses: measles, RSV and mumps. The expression of this gene was enough to drive the infections to extinction after a number of replication cycles.  This inhibition was independent of the previously known cytosine deaminase activity during HIV infection however it did result in impaired transcription and also increased mutation rates. The reasons for these remain to be found to date but it may involve direct binding to viral RNA molecules (genomes). 

A number of questions still have to be addressed:

• Does this occur during physiological (ex vivo/in vivo) conditions? It has been shown to be expressed in some epithelial cells, definitely in T cells and macrophages, which play a role in infection with these respiratory viruses? This work did show it in measles virus T cells but how about lung epithelial cells?
• If previous activity was linked to DNA binding, how does this APOBEC3G interact with these viral RNAs? Does this RNA binding activity happen during HIV infection?
• How does APOBEC3G induce increased mutation frequency independent of it's known activities?
• Do these viruses not encode genes that protect against APOBEC3G inhibition? If they don't, why don't they?

Fehrholz M, Kendl S, Prifert C, Weissbrich B, Lemon K, Rennick L, Duprex PW, Rima BK, Koning FA, Holmes RK, Malim MH, & Schneider-Schaulies J (2011). The innate antiviral factor APOBEC3G targets replication of measles, mumps, and respiratory syncytial virus. The Journal of general virology PMID: 22170635