PROJECT SUMMARY Although the rate of new HIV infections has decreased, containment and eventual eradication of the HIV pandemic remains a top priority in contemporary biomedical research. One of the major challenges to HIV cure is the need to restore normal immune function in order to effectively eliminate the established viral reservoir. We have assembled in RID-HIV: “Reversing Immune Dysfunction for HIV-1 eradication”, basic and clinical scientists with expertise in virology, immunology, microbiome biology, epigenetics, and systems biology. In addition, Merck Research Laboratories will invest significant intellectual, human and material resources to complement the efforts of the academic scientists. The RID-HIV Collaboratory will collectively function to explore the underlying basis of the immune dysregulation in HIV-infected individuals and the impact it has on reservoir persistence and viral rebound control. We will test for the first time several innovative concepts, including identifying epigenetic mechanisms imprinted by the microbiome and host and bacterial metabolomes that prevents the development of effective innate and adaptive immune responses that can control the size, quality and anatomical localization of the HIV reservoir. The overarching goal of the RID-HIV Collaboratory is to provide preclinical in vivo proof-of- concept for a therapeutic paradigm that encompasses immune restorative treatments, used in concert with enhanced viral reactivation and elimination strategies, in order to deliver a HIV-1 cure. We propose three highly integrated and complementary scientific Research Foci (RFs), to be supported by rigorous and iterative modeling of outcomes and shaped by our outreach to the HIV community. In RF1 we will investigate the mechanisms whereby host- and microbiome-derived metabolites impact innate immune responses and influence the maintenance of the latent viral reservoir. In RF2 we will pursue the hypothesis that in ART/ATI clinical cohorts, metabolites that govern innate immunity shape the adaptive immune responses that could prevent viral rebound upon 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 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. In RF 3 we 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 that enhance reservoir clearance. Finally, gene editing will be deployed for in vivo targeting and elimination of latent provirus not amenable to LRAs. The outcomes of studies in RF1, RF2 and RF3 will enable the synthesis of a predictive mathematical model to establish the most likely combinations of therapies to achieve an HIV-1 cure, and which will be tested in a capstone aim to establish proof-of-concept for these strategies in NHP models and to enable translation to the clinic.

PROJECT NARRATIVE While antiretroviral therapy (ART) has achieved remarkable success, with AIDS patients now living long, full lives, HIV-1 infection remains incurable due to the presence of a persistent viral reservoir, capable of rebounding upon interruption of treatment. The RID-HIV (Reversing Immune Dysfunction for HIV-1 eradication) Collaboratory brings together leading university scientists from more than twelve academic institutions as well as Merck Research Laboratories, with the goal to understand the molecular and cellular basis for the loss of immune homeostasis in HIV infected patients. This knowledge will be harnessed to create a therapeutic paradigm encompassing immune restorative treatments, utilized in concert with enhanced viral reactivation and elimination strategies, to establish a HIV-1 cure.