Giving exhausted immune cells a fighting chance against chronic HIV infection

Researchers have found a new way to combat immune exhaustion from chronic HIV infection.

The exhausted immune cells are inhibited by proteins on their surface, the new PLOS Pathogens study suggests restoring immune function by interfering with negative signals transmitted by these inhibitory proteins. We speak with the authors of the study, Andreas Meyerhans and Jordi Argilaguet from the University Pompeu Fabra, Barcelona. 

ResearchGate: What is the relationship between HIV infection and immune exhaustion?

Andreas Meyerhans & Jordi Argilaguet: Any infection that persists over a long period of time like HIV leads to immune exhaustion, a phenomenon characterized by dysfunctional specific killer cells. Exhaustion is mediated by inhibitory proteins like PD-1 on the cell’s surface and reduces the immune’s control over virus expansion.

RG: What was your study about?

AM & JA: Today, HIV can be nicely controlled by antiviral drugs. However, these drugs fail to eliminate HIV from an infected individual, they cause side effects and are a significant financial burden on the health system. To have a chance at controlling HIV without the need of continuous drug administration we need to shift the immune system/virus balance more towards virus control. This can be achieved, at least theoretically, by reversing exhaustion and increasing effector cell function. In our study of blood cells from different HIV patient groups, we examined the effect of anti-PD-L1 antibodies that inhibit the negative signaling of PD-1 on effector and regulatory T cells (Treg).

RG: What were your results?

AM & JA: We found that antiviral immune control can be augmented only when the virus load was well controlled in HIV-infected individuals i.e. by antiviral drugs. In that case, PD-1/PD-L1 pathway blockage led to an expansion of anti-HIV killer cells over Treg cells. Treg cells are suppressive white blood cells that are also subject to the same inhibitory pathway regulation.

In contrast, when blood cells from viremic HIV-infected individuals were analyzed, Treg cells expanded efficiently and thus reduced the effector to regulatory T cell ratio that controls HIV. Taken together, our data points to Treg cells as an important component in the outcome of PD-1/PD-L1 pathway inhibitor therapies and suggests a net gain in anti-HIV immune responses only when the HIV loads are well controlled during the administration of these novel compounds.

RG: What is the PD-1/PD-L1 pathway?

AM & JA: PD-1 and PD-L1 are cell surface proteins that can interact with each other. When they do so, PD-1 sends negative signals into an effector or a regulatory cell that inhibits its function. In colloquial terms this signal can be thought of as a sleeping pill that puts the cell to sleep. In reverse, stopping this interaction by antibodies wakes the cells up.

RG: What does this mean for future HIV research?

AM & JA: Our results predict that the virus load is a critical parameter in restoring immune effector function. It is now important to establish in clinical trials (i) whether our ex vivo measures are good predictors for treatment outcome, (ii) whether these PD-1/PD-L1 pathway inhibitors show a long-term patient benefit in shifting the virus/immune system balance towards better virus control even without antiviral drugs, and (iii) whether their combination with therapeutic vaccines result in an enhanced immune response.

Featured image courtesy of NAID.