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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 macaques. 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. Using in vivo adaptation we have recently generated a virus that is highly pathogenic in macaques causing profound CD4+ T-cell depletion and AIDS-defining opportunistic infections and/or lymphoma. Interestingly, the adapted virus Vpu protein acquired the ability to antagonize macaque tetherin and disease progression could be determined by manipulating CD8 cells early during infection. This is the first time that HIV-1 causes AIDS in a non-hominid species.

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 have developed a novel strategy for generating large number of SHIV constructs expressing Env proteins derived from HIV-1 strains transmitted in humans, transmitted/founder (T/F) viruses. By inoculating animals with cocktails of multiple SHIVs we have selected variants that can replicate and cause disease in animals without requiring animal-to-animal passage, an important milestone for unadapted R5-SHIVs.
Further development of these animal models could substantially facilitate the evaluation of novel clinical HIV-1 therapies, prevention strategies and interventions for virus eradication.

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