Impact of metabolic programing of T cells from the GI tract and related tissues on HIV reservoir seeding, maintenance and reactivation

Two cases of virus eradication (the “Berlin patient” and the “London patient”) demonstrated that a cure for HIV
infection is feasible. Meanwhile, the burden of the HIV epidemic, which spreads unabated, as such that for every
person living with HIV (PLWH) that starts antiretroviral therapy (ART), two new people become infected, fuels
the global consensus that a cure for HIV is needed to curb the epidemic. Limitations towards eradication are: (i)
HIV persistence in latently infected cells invisible to immune responses, (ii) inability of a damaged/exhausted
immune system to eliminate HIV-infected cells, and (iii) a state of chronic inflammation (INFL) that persists
despite ART. A better understanding of HIV reservoir seeding, maintenance and reactivation will identify new
strategies for effective virus eradication. We reported that diet may interfere with SIV replication, immune
activation (IA)/INFL, microbiome, basic metabolic features, and disease progression. Diet impacts directly and
indirectly the host metabolism, modulating immune responses and the prognostic of HIV infection. We also
reported a major impact of cell metabolic programing on all the key aspects that drive HIV persistence: (i)
susceptibility to infection of HIV targets, persistence of infected cells, and the establishment of latency. (ii) Quality
and magnitude of the immune responses to HIV. (iii) INFL associated to HIV infection, that contribute to reservoir
maintenance (through continuous proliferation of latently infected cells) and its replenishment in tissues. Finally,
we reported that metabolic alterations of the immune cell programing can preferentially occur in the gut.
Altogether our results studies define an axis (diet→microbiome→nutritional metabolism→immunometabolism)
that can dramatically impact HIV pathogenesis and shape HIV reservoir seeding, maintenance and reactivation,
and which can be fueled by diet. Fasting and dietary interventions are being currently explored, alone or in
combination with metabolic inhibitors in multiple other pathological conditions. We will probe the hypothesis
that administration of a Western diet (WD, i.e., rich in fat and sugars) to rhesus macaques will fuel SIV
reservoir formation, maintenance, and reactivation, through changes in T cells from the gut and related
lymphoid and AdTs. We will assess the overall impact of the WD on host microbiome, metabolism, immune
cell metabolic programing, immune responses, IA/INFL, and we will correlate these parameters with reservoir
seeding, maintenance and reactivation. We will further determine whether gut T cells are responding to either a
change in dietary sugars and lipids, plasma sugar and lipid increases trigerred by the WD, or to known changes
in gut microbiome driven by WD. We will also therapeutically revert the WD-related processes with statins. Since
the key alterations reported in our preliminary studies appeared to be centered by the gastrointestinal (GI) tract,
the main site of HIV replication and CD4+ T cell depletion, we will focus on the gut and the adjacent lymphoid
and AdTs. Blood will be used as a systemic comparator to alterations in the GI area. These studies may identify
new strategies to curb the HIV reservoir, reverse the metabolic dysfunctions and control residual INFL.

Grant Number: 5R01DK131476-04
NIH Institute/Center: NIH
Principal Investigator: CRISTIAN APETREI