Immunotherapy against cancer to be used in HIV cure strategy: a proof-of-concept
In the era of suppressive antiretroviral therapy (ART), HIV reservoir cells are the last hurdle in eradicating the virus. Here, we are testing the hypothesis that immunotherapy against cancer potentiates the reactivation of latently infected cells isolated from ART-suppressed individuals favoring their elimination.
The HIV/AIDS pandemic represents one of the most important global health challenge in modern history. Even if antiretroviral therapy (ART) can effectively control HIV replication, it is not curative. To lighten the burden of lifelong therapy on people living with HIV, groups of researchers work toward the development of new strategies to cure HIV infection (Deeks et al, Nat. Med. 2016). The major barrier to HIV eradication is the persistence of HIV in long lived cells during ART. Our research group is focusing his efforts on the understanding of the immunological mechanisms of HIV persistence with the objective of developing novel interventions to reduce and control the HIV reservoir pool.
The study published in Nature Communications (Fromentin et al, Nat Comms 2019) is the result of a collaborative work that started more than 10 years ago when Nicolas Chomont was postdoctoral fellow in Rafick-Pierre Sekaly’s lab. They decided to test the impact of a blocking antibody for PD-1 on HIV replication. At this time, Nicolas’ bench neighbour, Lydie Trautmann, was characterizing PD-1 as marker of exhaustion on HIV-specific CD8+ T cells during HIV infection. She demonstrated that PD-1 blockade can rescue HIV-specific CD8+ T cell functions (Trautmann et al, Nat Med 2006). On his side, Nicolas added the PD-1 blocking antibody to CD4+ T cells isolated from the blood of viremic individuals, which surprisingly, resulted in an increase in viral production in ex vivo cell culture. The long journey to our recently published manuscript started this day. It took several years, collaborations with researchers and pharmaceutical company from the US, Australia and Canada and high dedication of people living with HIV who participated in our study to understand this initial observation.
A few years later, I, as a postdoctoral fellow in the newly established Chomont lab, identified several immune checkpoint molecules as marker of HIV infected cells during ART, namely PD-1, LAG-3 and TIGIT (Fromentin et al, PLoS Path 2016). Together with other lab members, I repeated the initial observation performed with cells from treated individuals. This work demonstrated that PD-1 was not only a marker of HIV infected cells during untreated and treated HIV infection, but it was also actively promoting HIV silencing. Indeed, the engagement of PD-1 inhibited viral production at the transcriptional level and abrogated T-cell receptor (TCR)-induced HIV reactivation in latently infected cells isolated from virally suppressed individuals. In this study, we also enlightened the molecular mechanisms by which this phenomenon occurred. The natural next step was to evaluate if PD-1 blockade with a monoclonal antibody could revert HIV from latency. The association with a leading pharmaceutical company in immunotherapy against cancer, Merck, allowed us to access to pembrolizumab, one of the two immune checkpoint blockers (ICBs) for PD-1 being approved to treat cancer. We observed that PD-1 blockade greatly enhanced HIV reactivation induced by standard latency reversal agents (LRA).
Our findings support the idea to combine LRAs with immunotherapy to facilitate the reduction of the HIV reservoir. Going further it will be essential to carefully evaluate the safety and the efficacy of such strategies in people living with HIV and who are virally suppressed on ART. Currently, several clinical trials evaluating the safety of ICBs in people living with HIV and with cancer are ongoing.
This paper would not have been possible without the dedication of the study participants and the highly collaborative network of researchers. It is also a nice demonstration of the richness of the connections between different fields of research: Pioneering work from the cancer field fed the HIV eradication field. Hopefully, these connections will lead to the development of additional innovative concepts that will benefit both fields.