World Premiere: Diaccurate reveals the mechanism of immune disablement in HIV infection
PUBLICATION IN THE PRESTIGIOUS JOURNAL OF CLINICAL INVESTIGATIONS ON THE DISCOVERY OF CD4 ANERGY / CD4 LYMPHOPENIA IN HIV PATIENTS
- Discovery of a new mechanism of immune pathogenesis involving a phospholipase which becomes pathogenic for CD4+ T-cells in the presence of a viral peptide (cofactor)
- This new pathophysiological mechanism regulates the activity of CD4+ T-cells, the orchestrator of the immune system
- This article also describes a therapeutic monoclonal antibody to treat CD4+ anergy and lymphopenia
- These results pave the way for a new treatment strategy approach promoting a remission of HIV infection, potentially also applicable to the treatment of certain cancers
“Thirty-seven years after the discovery of HIV, the mechanism of AIDS-related immunosuppression was still poorly understood. Our discovery shows how the virus cooperates with the patients’ enzymes to disable lymphocytes and neutralize the immune response,” explained Prof. Jacques Thèze, co-founder and CEO of Diaccurate.
“We are excited by the discovery of this new “decoy” mechanism exerted on the immune system, which is probably implicated in several other infectious diseases and cancers. Diaccurate’s anti-PLA2G1B monoclonal antibody, PLAZUMAB, could help restore the immune system’s normal activity, thereby helping patients fight viruses or cancer cells more effectively. Truffle Capital is proud of the creation of Diaccurate in partnership with Jacques Thèze, in line with its early-stage selection model - at the patent filing stage - of breakthrough innovations in biotechnologies and medical devices potentially leading to ground-breaking changes in healthcare,” declared Dr. Philippe Pouletty, Chairman of Diaccurate and CEO of Truffle Capital.
“The mechanism disabling CD4+ T-cells in HIV-infected patients was still unknown. In this issue of The Journal of Clinical Investigation, Prof. Jacques Thèze and his team at Diaccurate Laboratories report on an important discovery for HIV therapy. For the first time, Diaccurate demonstrated that the binding of an endogenous phospholipase A2 Group 1B enzyme (PLA2G1B) with the HIV gp41 protein triggers pathogenic effects in CD4+ T-cells. This newly-identified mechanism helps explain both CD4+ anergy and lymphopenia, these effects being hallmarks of HIV-induced immunodeficiency,” said Prof. James Whitney, Harvard Medical School and Beth Israel Hospital in Boston, USA.
“This major breakthrough opens novel therapeutic avenues to restore CD4+ T-cell function and boost the immune system of HIV-infected patients. Diaccurate has fully characterized a humanized monoclonal antibody that neutralizes PLA2G1B and could thereby help reverse HIV-associated pathogenic processes,” said Prof. Jean-Pierre Routy, McGill University and Royal Victoria Hospital in Montreal, Canada.
Human Immunodeficiency Virus (HIV) Worldwide
- 36.9 million people live with HIV
- 6,000 people discover their HIV status every year
- 21.7 million people receive a treatment
- Over 170.000 people live with HIV in France
AIDS (Acquired Immunodeficiency Syndrome) is a disease of the immune system caused by the Human Immunodeficiency Virus (HIV). This virus targets specifically the host’s lymphocytes (particularly CD4+ T-cells), a type of white blood cells which play a key role in the immune function. However, less than 0.5% of these cells are infected by the virus, and yet all CD4+ T-cells become dysfunctional which renders the immune system ineffective, thereby allowing HIV infection to prosper and leaving the body vulnerable to other infections and cancers. HIV-infected patients can be treated effectively with antiviral drugs provided they are taken for life, because their immune system is unable to eliminate the virus which will start replicating again as soon as the treatment is stopped.
The disablement of CD4+ T-cells plays a critical role in the severe immunodeficiency associated with HIV infection, via two mechanisms:
- CD4+ T-cells become ineffective, particularly unresponsive to certain antigens and cytokines (CD4 anergy)
- Their numbers are reduced (CD4 lymphopenia)
Although the role of CD4+ T-cells is well known, a question was still unanswered:
- Why then, when less than 0.5% of CD4+ T-cells are infected, are all these cells dysfunctional?
Diaccurate published today a study highlighting the role of a protein (PLA2G1B enzyme, which is produced naturally by the pancreas) in the generalized disablement of CD4+ T-cells. In HIV-infected patients, a virus fragment (acting as cofactor) weakens CD4+ T-cells, and the PLA2G1B enzyme then attacks the cell membrane, which becomes “bumpy” due to its membrane proteins clumping together instead of being evenly distributed. This deformation of the membrane blocks CD4 receptors and the cells can no longer fulfil their regulator role. The immune system is thus disabled and the immunosuppressed patients are unable to fight other infections or cancers, which can lead to their death.
The discovery of this deformation of the membrane of CD4+ T-cells in HIV patients and of the role played by the PLA2G1B enzyme paves the way for a new type of treatment for HIV patients. Diaccurate announced in this publication its development of a humanized monoclonal antibody (mAb), currently in preclinical stage, capable of neutralizing the PLA2G1B enzyme (Plazumab) to reverse CD4 hypo-reactivity (anergy) and lymphopenia.
Diaccurate has been granted an exclusive worldwide licence by Institut Pasteur on the original patent which led to the creation of the Company by Truffle Capital.
Announcement of the publication in the Journal of Clinical Investigations
Diaccurate SAS announced today the publication of data demonstrating the pathogenic potential of an endogenous Phospholipase A2 Group 1B enzyme (PLA2G1B). The results of the study conducted by Prof. Jacques Thèze and the Diaccurate team in collaboration with Institut Pasteur, CNRS, Inserm, University of Madrid, University of Seville and Scripps Research Institute (USA) were published yesterday in an article entitled “PLA2G1B is involved in CD4 anergy and CD4 lymphopenia in HIV-infected patients” in the online issue of the prestigious peer-reviewed Journal of Clinical Investigations
Until this discovery, it was unclear why uninfected CD4+ T-cells would become dysfunctional, leading to severe immunodeficiency in HIV-infected patients. In the article, the authors show that more than 80% of CD4+ T-cells from HIV-infected patients have morphological abnormalities (bumpy cells). Their membrane showed numerous abnormal membrane microdomains (aMMD), which trap and inactivate physiological receptors, such as that of Il-7.
In patients’ plasma, the enzyme PLA2G1B was identified for the first time as the key molecule responsible for the formation of aMMDs. Under physiological conditions, PLA2G1B was shown to bind to the gp41 HIV envelope protein, which targets PLA2G1B on the surface of CD4+ T-cells. The PLA2G1B/gp41 pair inhibits the response capacity of CD4+ T-cell (anergy). At high concentrations in vitro, PLA2G1B can inhibit alone, independently of gp41, IL-2, IL-4, and IL-7 responses, as well as the activation of CD4+ T-cells. PLA2G1B also decreased CD4+ T-cells survival, thereby likely contributing to CD4+ lymphopenia in these patients. The effects on CD4 T-cell anergy were shown to be blocked by Diaccurate’s humanized monoclonal antibody (Plazumab) neutralizing specifically the enzyme PLA2G1B in vitro and in vivo. Consequently, the PLA2G1B/gp41 pair is a primary therapeutic target to stimulate immune responses and, potentially, an important new treatment for HIV-infected patients.
Diaccurate thus discovered a fundamental aspect of anti-HIV immunity: an endogenous enzyme PLA2G1B and an HIV-specific cofactor that induce CD4+ T-cell hypo-reactivity (anergy) and reduction in number (lymphopenia). Diaccurate developed a humanized monoclonal antibody (Plazumab) that neutralizes the endogenous enzyme and reverses CD4+ hypo-reactivity. This monoclonal antibody has entered its regulatory preclinical development stage. Multiple additional therapeutic indications are possible for other diseases involving PLA2G1B and a cofactor specific of the pathogen (i.e. other infectious diseases and cancers).