With 35 million HIV-infected individuals worldwide, containment and eventual eradication of  AIDS remains a top priority in biomedical research. Although ART adherence leads to durable virus control, the  persistence of long-lasting latent HIV reservoirs means that rapid virus rebound occurs if ART is withdrawn.  Moreover, treated HIV-infected adults have a higher risk of several non-AIDS-related morbidities and greater  mortality than age-matched uninfected adults. Therefore, the development of a curative strategy for HIV-1 is a  critical component of improving the outcomes for individuals impacted by the HIV/AIDS pandemic.  Although ART profoundly suppresses viral replication, there is abundant evidence that the immune 
system is not fully restored, resulting in the observed lack of control of viral replication upon cessation of therapy. 
This immune dysregulation in HIV-infected individuals likely involves multiple components of the immune system, 
from the gut microbiome, to innate immune subsets, to effector and helper adaptive immune functions. The
members of the RID-HIV (Reversing Immune Dysfunction for HIV-1 eradication) Collaboratory will work together
to understand the underlying basis of this immune dysregulation and the impact it has on reservoir persistence
and control of viral rebound. Critically, these studies are designed to deliver novel therapeutic approaches to 
restore antiviral immune responses and overall immune cell homeostasis. In addition, the Collaboratory will 
optimize and validate leading-edge pharmacological, genetic, and cell-based strategies to reverse HIV-1 latency, 
promote immune-mediated killing of reactivated infected cells, and target the provirus for genetic inactivation to 
further debulk the viral reservoir that is not amenable to reactivation. Thus, the overarching goal of the RID HIV Collaboratory is to provide preclinical in vivo proof-of-concept of the efficacy of a therapeutic  paradigm that combines immune restorative treatments with enhanced viral reactivation and elimination  strategies, in order to deliver a HIV-1 cure. To do this, we have recruited highly experienced scientists with a  history of long-term collaborations, including our corporate partner Merck, who will provide expertise and tools  critical for our objectives. We propose three highly integrated and complementary scientific Research Foci (RFs),  as required by RFA AI-20-035, to be supported by rigorous and iterative mathematical modeling of outcomes, and shaped by our interactions with the HIV community.