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Current Research

Scientific Overview


Theodora Hatziioannou
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Theodora Hatziioannou, Ph.D.
Associate Professor

The main goal of our lab is to discover the factors that limit the species tropism of primate lentiviruses and to use this knowledge to develop an HIV-1-based virus that can replicate and cause disease in macaques. Current animal models using SIV or SIV-derived viruses are very useful but also have serious limitations in studies and development of both drugs and vaccines. Our approach to generating an HIV-1-based animal model has been to understand the barriers to HIV-1 replication in macaque cells, engineer the virus so it can overcome them and then test the resulting virus variants in vivo. Thus far, this approach has been rather successful in that we have been the first to generate a virus almost entirely derived from HIV-1 (~94% of the genome), termed simian tropic HIV-1 (stHIV), that is capable of establishing high levels of acute viremia in pigtail macaques and persisting for several months post-inoculation. Although this constitutes a significant breakthrough towards our ultimate goal, stHIV is not pathogenic in animals. Therefore, our current efforts are focusing on improving stHIV replicative capacity and ability to cause disease in vivo.

Recently, we have identified macaque Tetherin, a protein whose expression is induced by IFN, as a potent inhibitor of HIV-1 particle release that, unlike its human counterpart, cannot be overcome by HIV-1 Vpu. We have also shown that most SIVs that do not express Vpu use Nef to overcome Tetherin from their host species. Additionally, we have demonstrated that Nef recruits AP-2 to downregulate Tetherin and rescue particle release. We have also determined the anti-Tetherin activity of both Vpu and Nef proteins from a wide range of SIVs and have shown that Vpu proteins from the SIVdsn/mus/mon lineage are capable of counteracting macaque Tetherins. These findings are being incorporated in the generation of novel stHIV variants.

Another area we are currently working on is the generation of stHIV and SHIV variants that use the CCR5 co-receptor (R5-tropic). Given that most primary HIV-1 isolates are R5-tropic there has been a long effort to develop R5-tropic SHIVs that are consistently pathogenic in animals yet the number of such chimeras is currently very limited. We aim to generate R5-tropic stHIV/SHIVs that closely represent the HIV-1 Envs found in transmitted viruses in humans, that can replicate in rhesus macaques. If successful, this project has the potential to greatly facilitate the investigation of interventions that target mucosal transmission as well as treatment/vaccination strategies.

Our lab works very closely with those of Paul Bieniasz at ADARC and Vineet Kewal Ramani and Jeff Lifson at NCI, Frederick.