The persistence of a reservoir of long-lived, latently infected cells carrying replication-competent proviral DNA constitutes the main barrier to Human Immunodeficiency Virus type 1 (HIV-1) cure. Recent research on HIV cure has focused strategies to "purge" the viral reservoir either to eradicate the infection or, at least, delay the time to viral recrudescence after antiretroviral treatment (ART) interruption. On the other hand, chronic HIV-1 infection is characterized by a dysfunctional state of CD8+ T cells.
A long-standing approach has been the establishment of latency reversal (LR) strategies, aiming to pharmacologically reactivate viral expression in latently infected cells, exposing them to clearance by CD8+ T cells or death through viral cytolysis. Strategies have also been developed to stimulate virus-specific CD8+ T cells. This global approach is called "shock-and-kill".
PD-1 blockade has been shown to be able to both facilitate LR and reverse CD8+ T cell dysfunction in HIV-1 ex vivo.
Clinical studies evaluating PD-(L)1 blockade in people living with HIV (PLWHIV) without cancer provide promising evidence for both immunologic and virologic response but also highlight the main limitations of immune checkpoint blockade (ICB) in PLWHIV: variable and transient responses to the treatment, and a safety concern. Combination with other ICB would be a relevant approach.
Anti-GARP:TGF-β1 monoclonal antibodies overcome resistance to anti-PD-1 immunotherapy in murine models of cancer, resulting from the increase in numbers or effector functions of anti-tumor CD8+ T cells. These findings have been subsequently translated into clinical research, with a phase I first-in-human study in patients with solid tumors.
In HIV-1 infection, TGF-β1 is involved in disease progression and pathogenesis, notably in the establishment of the reservoir. The inhibition of TGF-β1 receptor by its inhibitor (galunisertib) has been shown to increase LR in HIV ex-vivo as well as in a in-vivo model with SIV. In the simian model, galunisertib also enhanced anti-SIV immune response and decreased SIV reservoir size.
This study will assess, in an ex vivo model, whether the addition of GARP:TGF-β1 blockade to PD-1 blockade enhances the virologic and/or immunologic responses, in a shock-and-kill combined strategy.
Adults (min 18 years old).
HIV-1 subtype B infected and regularly followed at Centre de reference HIV of Cliniques Universitaires Saint-Luc.
Treated on cART and virologically suppressed.
Elite controlers
Recent viral blip (defined as HIV-1 viral load in plasma 30-200 copies/ml, < 6 months prior to study inclusion)
Chronic hepatitis B or C co-infection.
Acute illness at the time of inclusion.
Single group
blood drawn
Other interventionblood drawn
HIV-1 reservoir shrinkage
To assess the additive and/or synergistic effect of GARP:TGF-β1 blockade when added to PD-1 blockade in terms of LR and enhancement of HIV-specific T cellular response in HIV-1, in order to evaluate the benefit of a combined immunotherapy as a "shock-and-kill" treatment aiming towards HIV cure.
reversal of immune exhaustion
The reversal of immune exhaustion will be assessed after PBMCs culture and peptide stimulation, by measuring by flow cytometry the expression of cytokines indicative of effector activity and of markers of immune exhaustion on different subsets of cells.
Latency reversal
Latency reversal will be assessed after PBMCs culture and peptide stimulation, by measuring the released HIV virions by HIV-1 RNA (ddPCR) and p24 antigen (ELISA) in the ultracentrifuged supernatant of PMBCs cultures.
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