AIDS remains an incurable global pandemic that is becoming more resistant to available treatments. Current treatments for those suffering from HIV/AIDS involve of a combination of anti-retroviral drugs targeting the HIV protease, reverse transcriptase, and integrase proteins, as well as a number of newer therapeutic targets. Combination therapy significantly reduces the rate at which resistance develops, however, no cure is currently available and with increasing HIV resistance, the development of new treatment strategies targeting the HIV virus continues to be a priority.
Human Apobec3G (A3G) and HIV viral infectivity factor (Vif) proteins are key determinants of HIV infectivity. One new treatment strategy could involve developing small molecules that inhibit interactions between Vif and A3G (Figure 1).
Figure 1. Original and New Models of APOBEC3G Antiviral Action. Panel A depicts the original model of APOBEC3G action. In a cell producing virus lacking functional Vif protein, APOBEC3G incorporates into nascent viruses budding from the producer cell (top of panel). When the virus infects a target cell (bottom of panel), APOBEC3G is released and mutates the nascent DNA, leading to its degradation or hypermutation. If Vif is present in the producer cell (top of panel), APOBEC3G is tagged with ubiquitin for transport to the proteasome and destruction. Panel B depicts a new mechanism by which a low molecular mass form of APOBEC3G (LMM APOBEC) inhibits virus. LMM APOBEC is found in resting CD4+ T cells and can block events in viral replication immediately following fusion through a mechanism yet to be determined. It can operate on wild-type virus in the presence of functional Vif protein. Panel C depicts another Vif-sensitive mechanism of APOBEC antiviral action uncovered by engineering a form of APOBEC that lacks DNA-mutating activity (APOBEC oval with X). Even in the absence of its mutational powers, APOBEC3G can demonstrate potent antiviral activity in the target cell. Where this block occurs in the viral replication cycle is still unknown. Figure originally published in the April-June 2005 issue of IAVI Report, see reference .
During reverse transcription A3G catalyses the deamination of cystosine bases to uracil in the nascent HIV cDNA reverse transcript. This leads to a high frequency of guanosine to adenosine mutations in the complementary DNA strand resulting in hypermutation of the HIV genome. This hypermutation ultimately destroys the coding and replicative capacity of the virus, and restricts HIV infectivity.
The innate anti-viral effects of A3G can be counteracted by Vif, which binds to and targets A3G for proteasomal degradation. Notably, HIV strains lacking Vif are incapable of causing infection. The long-term goal of this project is to obtain an increased structural and functional understanding of the interactions between A3G and Vif, and to use this knowledge to develop lead inhibitors that could become the basis of a new method of treating and possibly preventing HIV infection.
 Cohen, P. (2005) Guardian of the Genome: Research into a different kind of viral defense system may yield powerful treatments and solve some mysteries about HIV. IAVI Report. 9(2):1-5.