Multiomic analysis of ART-interruption cohorts identifies cell-extrinsic and -intrinsic mechanisms driving lymphocyte-mediated control of HIV rebound

The immunological mechanisms regulating HIV rebound after antiretroviral
therapy (ART) interruption remain unclear. We examined relationships
between host factors, HIV reservoir, and HIV time-to-rebound after
analytical treatment interruption (ATI) by characterizing pre-ATI
peripheral blood mononuclear cells (PBMCs) from 75 ART-suppressed people
with HIV (PWH) using high-parameter methods. Across interventional (CLEAR,
TEACH, REDUC) and non-interventional (A5345) cohorts, delayed rebound was
not associated with intact HIV. Cohort-specific immune effectors were
associated with delayed rebound. RNA sequencing of CD4+ T cells from A5345
revealed that mTOR inhibitor DDIT4 and zinc finger protein ZNF254 were
associated with delayed rebound. In vitro and in vivo studies demonstrated
that DDIT4 and ZNF254 suppressed HIV expression. Metformin induced DDIT4
and suppressed HIV expression in primary cells and cells from
ART-suppressed PWH, suggesting that this affordable diabetes drug could be
repurposed to silence HIV. Our results support pursuit of both immune- and
HIV-silencing strategies to achieve ART-free HIV remission.