Reversing Immune Dysfunction for HIV-1 Eradication

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.

Grant Number: 5UM1AI164561-05
NIH Institute/Center: NIH
Principal Investigator: SUMIT CHANDA