Host Cell Regulators of HIV Latency
The principle challenge to developing a cure for HIV is the persistence of the virus in long-lived latent reservoirs of quiescent CD4+ T cells, which must be either removed, disabled, or rendered non-infectious to prevent reemergence of the virus after treatment cessation. One of the most prominent strategies designed to achieve this end is known as “shock and kill”, whereby latently infected cells are induced to express the virus through treatment with latency reversing agents (LRAs) and subsequently cleared from the body. A number of LRAs have been described including T cell stimulatory agents, kinase activators, and chromatin modifiers, but these regimens have proven to be therapeutically untenable as they demonstrate incomplete penetrance and remarkable variability in their reactivation potential on a person-to-person, cell-to-cell, and provirus-by-provirus basis. This heterogeneity in reactivation potential is thought to arise due to the complex interaction between regulatory cis-acting elements near the site of proviral integration and the cellular milieu of trans-acting transcriptional regulators available in the cell. Unfortunately, the intrinsic host factors that influence these processes are poorly understood, especially in resting memory CD4+ T cells, which comprise a principle component of the latent reservoir.
In the Hultquist lab, we are using a new approach to edit the genomes of resting memory CD4+ T cells in order to better understand the genetic determinants of HIV infection and latency. We are finding that events early in the replication cycle can influence downstream events dictating latency establishment and maintenance in new and surprising ways. By better understanding the genetic factors that influence latency, we are hoping to inform HIV cure strategies that target this important yet enigmatic reservoir.
Active Projects:
- Optimize high-throughput editing platforms for various human primary cell types;
- Map the influence of targeted genetic factors on proviral integration and silencing;
- Arrayed screening of HIV host factors to determine latency correlates;
- Genetic and chemical epistasis mapping to determine functional relationships between LRAs and host factors.
Supported by the Gilead Sciences Research Scholars Program in HIV, the Third Coast Center for AIDS Research (P30 AI117943), and the National Institute of Allergy and Infectious Diseases (K22 AI136691). Previous funding was provided by the American Foundation for AIDS Research (amFAR) with the generous support of GenerationCURE (109504-61-RKRL).