AIDS has proven to be a stubborn foe that subverts our own defenses in ways never imagined. However, one positive byproduct of the AIDS epidemic is a remarkable number of insights into normal cell biology that have resulted from the intense study of HIV. As a case in point, scientists at the Gladstone Institute of Virology and Immunology discovered how HIV subverts an intrinsic antiviral factor in human cells. In doing so, they took a step toward the development of an exciting potential therapy for AIDS and, at the same time, gave us a glimpse into our own evolution. “APOBEC3G or A3G is an intrinsic antiviral factor that has the potential to stop HIV dead in its tracks. Unfortunately, HIV effectively counters these effects of A3G through the action of its Vif protein” said Warner C. Greene, director of the institute and senior author of the study. “By better understanding the interactions between this host factor and the virus, we may be able to interdict Vif's action and re-enable A3G's potent inhibition of HIV.” In previous work, Dr. Greene's laboratory showed that A3G made by the cell is incorporated into the new virus particles or virions as they are made. When the virus attempts to replicate itself in the next infected cell, A3G massively mutates the nascent viral DNA, rendering the virus nonviable and ending the infection. However, HIV uses its Vif protein to partially block the production of new A3G and greatly accelerate the intracellular degradation of existing A3G in the proteasome. Thus, there is no A3G left in the cell for incorporation into virions, and the potent antiviral action of A3G is forfeited. Dr. Greene's laboratory went on to address another fundamental question about A3G. HIV virions enter cells that are laden with A3G. Why doesn't A3G residing in the cytoplasm of the cell undergoing HIV infection exert the same antiviral effects as A3G contained within the viral particle? The answer is that the cytoplasmic A3G is sequestered in very large RNA–protein complexes that are enzymatically inactive. The new research characterized these large complexes and provided some intriguing clues as to what these complexes and A3G do in the cell. After all, they existed long before HIV came into being and must have other functions.		A3G protects T cells in two ways. In resting CD4 T cells, a smaller version of A3G (LMM) blocks the reverse transcription (RT) of HIV-1 after the virus has fused with the cell, entered, and lost its protein coat (A). When the CD4 T cells are activated, endogenous retroelement RNAs are turned on. A3G appears to bind RNAs and recruit them into a large complex called the HMM. This HMM A3G blocks their “jumping” to new genetic locations (B). Although this action by A3G protects the cell from the retroelements, it also depletes the available A3G and leaves the cell exposed to infection by HIV-1 (C).
Dr. Ya–Lin Chiu in the Greene laboratory found that the complexes are very large (5–15 megadaltons). Using tandem affinity purification techniques coupled with mass spectrometry, the group identified approximately 95 different proteins and multiple RNAs within these

		complexes. Two of the complexes corresponded to staufen RNA–transporting granules and Ro ribonucleoprotein complexes. The staufen RNA granules are involved in transporting specific RNAs to select sites in the cell for their translation into protein. The story became even more fascinating when the RNA components were identified. Two of these RNAs corresponded to endogenous retroelement RNAs,
specifically Alu and hY RNAs. These RNAs are members of a larger family of mobile genetic elements that can jump from one place to another in human chromosomes. Such jumping, termed retrotransposition, involves a reverse transcription step, similar to that used by HIV. “Jumping genes” have been linked to various genetic mutations and cancer.

The Greene laboratory went on to show that recruitment of Alu retrotransposon RNAs into the large A3G complexes blocked the ability of these RNAs to undergo reverse transcription and thus limited their retrotransposition. “These findings identify a specific family of endogenous retroelement RNAs as the natural targets of A3G,” said Dr. Greene “A3G has been controlling the retransposition of these elements over millions of years and helping to protect the integrity of the human genome.” In the future, we may be able to identify small molecules that partially block the assembly of these large A3G complexes thus maintaining the strong protective effects against HIV afforded by unassembled A3G. However, the goal is to achieve a balanced production of		(l to r) Vanessa Soros, Ya–Lin Chiu, Mario Santiago, and Warner Greene
small and large forms of A3G to deal effectively with the internal threat posed by the retroelement RNAs while at the same time opposing infection by external retroviruses like HIV. In essence, the ultimate goal is for the cell “to eat its cake and have it too.” Chiu Y-L, Witkowska HE, Hall SC, Santiago M, Soros VB, Esnault C, Heidmann T, Greene WC (2006) High-molecular-mass APOBEC3G complexes restrict Alu retrotransposition. Proc. Natl. Acad. Sci. USA 103:15588–15593.