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Reversing Immune Dysfunction
for HIV-1 Eradication
The RID-HIV Collaboratory “Reversing Immune Dysfunction for HIV-1 Eradication” is part of the Martin Delaney Collaboratories for HIV Cure Research, the flagship NIH program on HIV cure research.
Although the rate of HIV transmissions has decreased, an eventual end to the HIV pandemic remains a top priority in biomedical research. A central hypothesis in the RID-HIV Collaboratory is that normal immune function will need to be restored in people living with HIV in order to empower them to eliminate established viral reservoirs and achieve a cure.
RID-HIV is exploring the underlying basis of the immune dysfucntion in people living with HIV and the impact it has on HIV persistence and viral control. We will test several innovative concepts, including identifying mechanisms by which the microbiome, and host and bacterial metabolomes, prevent the development of effective innate and adaptive immune responses that can control the size, quality, and anatomical localization of the HIV reservoir.
The Collaboratory will also identify pharmacological methods to enable reversal of this immune dysfunction caused by HIV-1 infection. In combination with the development of next-generation latency reversal agents (LRAs) and novel elimination strategies, we propose to provide preclinical in vivo proof-of-concept for a therapeutic paradigm that could deliver an HIV-1 cure.
The RID-HIV Collaboratory is led by Sumit K. Chanda, PhD (Scripps Research), Paula Cannon, PhD (University of Southern California), and Rafick Sékaly, PhD (Emory University).
RID HIV Research Focuses
The Collaboratory comprises three highly integrated and complementary scientific Research Foci.
Research Focus 1
Research Focus 1 will investigate the mechanisms whereby host- and microbiome-derived metabolites impact innate immune responses and influence the maintenance of the viral reservoir.
Research Focus 2
Research Focus 2 will pursue the hypothesis that metabolites that govern innate immunity thereby shape adaptive immune responses that could help prevent viral rebound upon ART treatment interruption. In addition, we will evaluate the capacity of engineered allogenic stem memory T cells to provide superior cognate help to promote the effector functions of antiviral CD8 T cells, and we will assess the ability of FDA-approved and novel immune modulators to reset this baseline immune dysfunction and enhance the function of this novel cell therapy product.
Research Focus 3
Research Focus 3 will optimize a best-in-class latency reversal agent (LRA) and identify clinical-stage molecules with synergistic LRA activity. Clearance of reactivated cells will be enhanced using a novel strategy for NK cell recruitment and by genetically modifying B cells to produce broadly neutralizing HIV-1 antibodies. Finally, gene editing will be deployed for in vivo targeting and elimination of latent provirus not amenable to LRAs.
The outcomes of the studies in these three Research Foci will be combined in a predictive mathematical model to establish the most likely combinations of therapies to achieve an HIV-1 cure. This will then be tested in a capstone project to establish preclinical proof-of-concept for these strategies and enable translation to the clinic.
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