Grant: Operating Grant - PA: HIV/AIDS Research Initiative - Biomedical/Clinical Stream

APOBEC3 proteins are best known as factors that have a protective role against HIV infection, also called restriction factors. These proteins can directly introduce deleterious mutations in the DNA of HIV upon cell entry, rendering it incapable of later spreading to new cells within the host or to new hosts. However, we have recently demonstrated that the mutator activity of APOBEC3 proteins is not required for specifically restricting the early stages of HIV infection. This underlies that APOBEC3 proteins employ several different strategies to prevent inhibit HIV replication. It is unclear at this time how exactly APOBEC3 proteins prevent HIV from inserting its DNA into a cell's genome at the early stages of the infection. We have recently made some important new findings in our quest to understand how APOBEC3 proteins work. Notably, we have identified 4 potential cofactors that may participate in restricting HIV infection. This grant renewal extends on these and other recent findings and has four major focuses: 1) further investigate how APOBEC3 proteins prevent retroviral integration in absence of DNA mutator activity; 2) determine if and how newly identified APOBEC3 interacting proteins are involved in HIV restriction; 3) carry out an in-depth analysis of a recently discovered ability of APOBEC3 proteins to disrupt the normal function of the HIV polymerase; and 4) develop new APOBEC3 mouse models to gain insight into the physiological and immunological relevance of our findings. We firmly believe that APOBEC3 proteins are promising candidates for inspiring the development of new types anti-HIV therapies. These strategies involve a new global approach that aims at recruiting and focussing the natural antiviral properties of the human innate system to prevent the infection and spread of HIV.