O'Doherty Laboratory

Studies in HIV: The introduction of antiretroviral therapy led to a rapid decline in viremia in HIV infected individuals and the eventual discovery of a latent HIV reservoir. This reservoir resides principally in long-lived memory T cells which can give rise to viral rebound when antiviral therapy is interrupted. Historically, it was thought that only activated CD4+ T cells could be infected with HIV. It was postulated that the HIV reservoir formed when infected activated CD4+ T cells returned to a resting state and became long-lived infected memory T cells. My team provided an alternate model for how latent reservoirs may form. Critically, we proved that resting T cells could be directly infected, debunking the idea that activation was necessary for HIV infection and reservoir formation. Debunking this dogma was important because that dogma led to a crippling bias in the field that only the memory T cells contributed to the reservoir. Ultimately by sequencing the HIV reservoir we obtained genetic evidence that direct infection of the most immature naïve T cells plays a critical role in reservoir formation and persistence. Moreover, our studies added to the evidence that the memory reservoir is neither silent nor stable; nor is it the only reservoir we need to target. This new view of HIV presents new challenges, but also new insights and opportunities for its cure.

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Current Projects:

1. Insights from a direct infection model led to a deeper understanding of the HIV reservoir.

2. Understanding the formidable naïve CD4 T cell reservoir

3. Uncovering the "not-so-stable" HIV reservoir in Memory CD4 T cells 

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Studies in Sickle Cell Disease:  Inflammation appears to be a major cause of morbidity in sickle cell disease. It is hypothesized that accelerated hemolysis incites the inflammatory process. One very effective therapy for sickle cell disease is red cell exchange, where sickled red blood cells are removed and replaced with wild type red cells that lack the mutation in beta-hemoglobin. This results in lower Hemoglobin S levels and potentially lower hemolysis. It follows that exchange treatment should theoretically lower inflammation, though this has not yet been directly tested.

 

Genetic therapies designed to reduce hemoglobin S similarly result in decreased hemolysis and should thereby decrease inflammation. In fact, in the first gene therapy trials the outcomes were remarkable in reducing levels of hemoglobin S and markers of hemolysis. They also reduced frequency of pain crises and hospitalizations improving quality of life. This good news was severely dampened by a high frequency of AML and MDS that developed in the first treated cohorts. Follow-up investigations suggested these cases of AML were not caused by the vector insertions. Consistent with inherent increased risk, individuals with sickle cell disease have a higher incidence of AML at baseline.  One potential explanation for this elevated risk could be that individuals with sickle cell disease have a stronger hematopoietic proliferative drive (Gondek, 2022). It will be critical to dissect the role of chronic inflammation vs chronic anemia in driving this process to advance these therapies. 

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Current Project:

1. Investigating white blood cell dynamics in individuals with Sickle Cell Disease