Small Molecule Inhibitors of Drug Resistant Forms of HIV-1 Integrase

Integrase strand transfer inhibitors (“INSTIs”) are currently in use as a component of prophylactic antiretroviral therapy for preventing HIV-1 infection from progressing to AIDS. Three INSTIs are approved by the FDA for inclusion in antiretroviral regiments: raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG). Clinicians have already identified several HIV-1 integrase mutations that confer resistance to RAL and EVG, and additional mutations that confer resistance to all three INSTIs has been identified in the laboratory.

Vaccines for HIV

The development of an effective HIV vaccine has been an ongoing area of research. The high variability in HIV-1 virus strains has represented a major challenge in successful development.  Ideally, an effective candidate vaccine would provide protection against the majority of clades of HIV.  Two major hurdles to overcome are immunodominance and sequence diversity.  This vaccine utilizes a strategy for overcoming these two issues by identifying the conserved regions of the virus and exploiting them for use in a targeted therapy. 

Biomarker signature development: microRNAs for biodosimetry

Alterations in microRNAs (miRNAs), a type of small non-coding RNAs, have been reported in cells/tumors subjected to radiation exposure, implying that miRNAs play an important role in cellular stress response to radiation. NCI researchers evaluated small non-coding RNAs, long non-coding RNAs (lncRNA), and mRNA, as potential non-invasive biomarkers for radiation biodosimetry. While the use of miRNAs as radiation biomarkers has been reported, the integrated use of miRNAs, mRNAs and lncRNAs to accurately determine radiation doses is novel and has not been published.

T cell tuning molecules that modify the immune response to cancer cells

Researchers at NIH/NICHD have identified approximately 200 proteins as candidate molecules (leads) that “fine tune” T cell receptor (TCR) signaling. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) seeks partners to collaborate on in vitro studies to validate these potential immunomodulators and to conduct in vivo studies in a murine cancer model to determine the effects of ligands (e.g. antibodies) to the proteins to determine their effect on the immune response to cancer cells.

Ex-vivo Production of Regulatory B-Cells for Use in Auto-immune Diseases

Regulatory B-cells (Breg) play an important role in reducing autoimmunity and reduced levels of these cells are implicated in etiology of several auto-inflammatory diseases. Despite their impact in many diseases, their physiological inducers are unknown.  Given that Bregs are a very rare B-cell, identifying factors that promote their development would allow in vivo modulation of Breg levels and ex-vivo production of large amounts of antigen-specific Bregs to use in immunotherapy for auto-inflammatory diseases.
 

Hydrocarbon Stapled Peptides that Inhibit the Linear Ubiquitin Chain Assembly Complex (LUBAC) for the Therapy of the Activated B Cell-like (ABC) Subtype of Diffuse Large B Bell Lymphoma (A Type of Non-Hodgkin’s Lymphoma)

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma and consists of three subtypes: activated B-cell (ABC), germinal center B-cell (GBC), and primary mediastinal B-cell (PMB). Despite advances in the front-line therapy for DLBCL, approximately one-third of patients will relapse. Substantially worse outcomes have been reported for patients diagnosed with ABC DLBCL and treated with standard chemoimmunotherapy, suggesting the need for novel strategies that improve treatment outcomes.