MINNEAPOLIS / ST. PAUL -- A human protein that mutates the AIDS virus (HIV) and holds potential for keeping the disease at bay has been discovered and its function described by a team led by Reuben Harris of the University of Minnesota. The new protein (called APOBEC3F) and one described previously (APOBEC3G) can directly mutate HIV. Such proteins--called retroviral restrictors--may contribute to HIV resistance in some people. Harris, an assistant professor of biochemistry, molecular biology and biophysics, and colleagues at the university report the discovery in a paper to be published online June 24 in the journal Current Biology.
In an individual infected with HIV, the virus uses the human cellular machinery to assemble new viral particles. But sometimes those particles contain time bombs: human APOBEC proteins that hitch a ride in the particles and mutate the virus' genetic material after it has infected a new host cell.
Unfortunately for us, the AIDS virus has evolved a counterdefense. It produces a protein called VIF (viral infectivity factor), which triggers the destruction of the retroviral restrictors, thereby preventing mutations from occurring. What scientists don't know is whether some HIV-resistant people have forms of the retroviral restrictor proteins that can evade VIF and avoid destruction.
When DNA from the HIV virus is inserted into the human genome, it sometimes bears the scars of encounters with the APOBEC proteins. The two proteins leave different mutational "signatures," and the signature of APOBEC3F occurs more often.
This, said Harris, indicates that it might be less vulnerable to the virus' VIF counterdefense. Indeed, using a model HIV system, Harris and colleagues showed that APOBEC3F was less susceptible to VIF than APOBEC3G. Moreover, said Harris, the two proteins can account for all the anti-HIV mutational signatures apparent in HIV DNA of AIDS patients. But what function the proteins perform in non-HIV-infected people is unknown. It is also unclear whether the defense mounted by the APOBEC proteins--when not foiled by VIF--would be enough to protect a person from AIDS.
"Strong APOBEC proteins may be a factor in HIV resistance," said Harris. "We need to discover whether these proteins are essential for keeping HIV at bay in an infected individual.
"APOBECs are a 'search and destroy' defense. It's different from the defense found in some HIV-resistant people, in which the outer surfaces of their cells no longer offer footholds for the virus to attach and begin the process of infection."
Here's how the APOBEC proteins are thought to work. When the core of an HIV particle enters a cell, it contains single-stranded RNA as its genetic material. This RNA must be copied into DNA because only DNA can be inserted into the host cell's genome. As the DNA strand is being synthesized, the APOBEC proteins mutate it by changing one of DNA's four bases--cytosine--to another base, uracil. But the DNA must be further copied to become double-stranded in order to insert itself into the human genome. The DNA appears to do this without incident, copying the mutations along with the original genetic information. Harris and others have observed that if VIF is not there to interfere, the two APOBEC proteins may mutate up to 25 percent of the cytosine bases in the HIV genome, wreaking havoc with its ability to continue the infection cycle.
The two APOBEC proteins differ in which cytosines in the first DNA strand they transform into uracil. APOBEC3G will transform the second of two adjacent cytosines. APOBEC3F, on the other hand, transforms a cytosine when it follows the base thymine. Harris and colleagues observed that the two APOBEC proteins are about equally potent mutators of the viral DNA in the absence of VIF.
"The outcome for the patient may depend in part on a seesaw-like balance between the APOBECs and VIF," Harris speculated.
The work was supported by a University of Minnesota start-up grant. Harris is a Searle Scholar and the recipient of a Burroughs-Wellcome Fund Hitchings-Elion Fellowship.
(C) University of Minnesota
POBEC3F Properties and Hypermutation Preferences Indicate Activity against HIV-1 In Vivo
Mark T. Liddament, William L. Brown, April J. Schumacher, and Reuben S. Harris
Current Biology. Published online Jun. 24, 2004
Zheng YH, Irwin D, Kurosu T, Tokunaga K, Sata T, Peterlin BM.
Human APOBEC3F is another host factor that blocks human immunodeficiency virus type 1 replication.
J Virol. 2004 Jun;78(11):6073-6.
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