Research Labs: Theodora Hatziioannou , Ph.D.
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Scientific Overview Non-Scientific Overview Theodora Hatziioannou:    CV    Personnel    Publications Return to Research Programs

HIV-1, the predominant cause of AIDS in humans, is unable to replicate in most nonhuman primate species. Therefore, most efficacy testing of vaccines and antiretroviral drugs is limited to difficult and expensive studies in human subjects. The most practical animal model consists of infection of rhesus macaques by SIVMAC or chimeras encoding the HIV-1 envelope (SHIV), both of which cause AIDS in these animals. This approach, however, is limited. Rhesus macaque cells express proteins, termed restriction factors, like TRIM5a and APOBEC3G, that specifically inhibit HIV-1 but not SIVMAC replication. Current work in my lab focuses on characterizing the effects of host cell restriction factors on virus replication and exploiting this knowledge to generate better animal models for HIV/AIDS.

We have demonstrated that restriction factors targeting the HIV-1  capsid and Vif proteins are solely responsible for the inability of HIV-1 to replicate in rhesus macaque cells in vitro. More importantly, through a series of engineering and adaptation steps we have generated a virus that is almost entirely derived from HIV-1 (~88%) that can replicate in primary rhesus macaque cells to levels comparable to SIVmac. This virus is named simian tropic HIV-1 (stHIV).

Currently my group is collaborating with Paul Bieniasz as well as groups at the NIH to test whether stHIV can replicate and cause AIDS-like disease in rhesus macaques. If so, stHIV has the potential to form the basis of a very widely applicable animal model of human AIDS, as it will overcome a great number of limitations of the models currently available.

The development of stHIV would not have been possible without the recent advancements in the field of host cell restriction factors that inhibit lentivirus replication. Although TRIM5a and APOBEC3G are major restriction factors of HIV-1 in rhesus macaque cells it is possible that other members of the TRIM and APOBEC families play a role in inhibiting HIV-1 replication and our goal is to identify these. This will facilitate the engineering of HIV-1 proteins that counteract all the restriction factors present in rhesus macaque cells, thus generating new versions of stHIV that are completely derived from HIV-1 sequences. Additionally, a related project aims to determine whether restriction factors have affected lentiviral zoonosis.