I4C 2.0: Immunotherapy for Cure

SUMMARY
The goals of I4C 2.0 are to advance our scientific understanding of the viral reservoir and to develop immunologic
strategies for HIV-1 remission and eradication by a highly collaborative and multifaceted research program
involving partnerships among academia, industry, government, and the community. Our overall hypothesis is
that multiple immunologic strategies will need to be explored and combined to achieve long-term, ART-
free virologic control or complete virus eradication, with the goal of selecting combination regimens to
advance into clinical development by the end of the proposed period of support. We propose three
Research Foci, a Management and Operations Section, and a Community Engagement Section.
Focus 1 (Mechanistic Basis of Reservoir Targeting and Viral Persistence)
Aim 1. To define a virologic, immunologic, and transcriptomic signature of viral persistence and rebound and to
determine how immunologic strategies target the viral reservoir in NHPs and humans
Aim 2. To define drivers of clonal expansion and persistence of the replication-competent viral reservoir in NHPs
and humans to enhance reservoir control and elimination
Focus 2 (Novel Strategies for Sustained Virus Remission)
Aim 1. To evaluate innovative immune engineering strategies that provide long-term T cell or Env-directed
immune control, including therapeutic vaccines, CAR-T cells, and engineered B cells
Aim 2. To combine approaches that augment humoral and cellular immune responses to achieve sustained
immunosurveillance and long-term ART-free virologic control
Focus 3 (Novel Strategies for Virus Eradication)
Aim 1. To evaluate innovative strategies for rapid elimination of the majority of the viral reservoir, including
improved LRAs combined with bNAbs, activated NK cells, and CAR-T cells
Aim 2. To combine the most effective approach to rapidly eliminate the majority of the viral reservoir with
sustained immunosurveillance to eliminate the residual viral reservoir
Management and Operations (MO) Section
Community Engagement (CE) Section

Grant Number: 5UM1AI164556-05
NIH Institute/Center: NIH
Principal Investigator: Dan Barouch