HIV: A Game of Immune Hide-and-Seek
While AIDS is no longer necessarily a life-threatening disease, a major obstacle to its recovery persists: the ability of HIV to conceal itself within the body, away from antiretroviral treatments. At Institut Cochin in Paris, Morgane Bomsel and her team are working to discover and describe these « hiding places » to enable the development of novel therapeutic and preventive strategies.
These days, when treated, acquired immunodeficiency syndrome (AIDS) is no longer a deadly disease. The discovery in the 1980s of effective treatments that prevent the proliferation of the virus responsible for the disease, HIV, have transformed the status of AIDS into that of a chronic disease. Antiretrovirals enable the immune system to recover after the onslaught of HIV, and to overcome the consequences of infection. The immune syndrome no longer develops and the long-term effects of the infection no longer make themselves felt. But this does not mean that the virus has gone away. We cannot say that there is a definitive cure. HIV remains hidden among the body’s cells in « reservoirs », inaccessible and protected, invisible to the immune defenses, and ready to bounce back. Behind the closed doors of Institut Cochin in Paris, Morgane Bomsel and her team have set about playing a veritable game of hide-and-seek with the evasive AIDS virus. Their aim is to better understand the sexual-infection and evasion mechanisms of HIV, particularly in the genital mucosa because as long as the virus remains invisible, it cannot be targeted and eradicated. Describing the reservoirs of HIV will make it possible to develop therapeutic and preventive strategies.
AIDS is a sexually transmitted disease. To understand how the virus infects and persists in the body, Bomsel started with the initial scenes of the crime: the sex organs. Today, the mechanisms of transmission by the mucous membranes during sex, particularly in the male genitals, and the genital immunity of the mucous membranes, remain poorly understood.
The team is working on cells in vitro and also with human blood and tissue, sometimes from people infected with HIV. The researchers receive foreskins from adults who are circumcised in the urology department of Cochin Hospital. Even penile tissue, retrieved from the reconstructive plastic surgery department of Tenon Hospital after sex reassignment surgery, is sent.
Circumcision reduces by 60% the risk of HIV infection in men during heterosexual sex. More than a decade ago, Bomsel’s team had shown that while the inner foreskin is one of the main gateways of the virus, it is not the only one. HIV also penetrates the penile urethra while other regions of the penis, such as the head of the penis or the end of the urethra, resist infection. When placed in contact with the virus, the explants of foreskin and urethra make it possible to visualize the stages of infection through the different tissue structures and the interactions of the virus with human tissue cells.
The team has shown that the Langerhans immune cells present in the stratified epithelium of the foreskin are among the first to capture HIV after it has penetrated the surface of the mucosa. Although somewhat resistant to infection with the virus, these cells will transmit, by means of contact, infectious particles to the white blood cells, specifically the CD4+ T cells in the tissues, which will migrate towards the blood. It is within these cells that HIV reproduces and takes up its lifelong hiding place in infected patients. But they are not the only reservoirs of the virus. Boxin Huang and the team are working to identify others.
In the urethral epithelium, while there are no Langerhans cells, there are other immune cells, known as macrophages. These are where Bomsel’s team found HIV in a dormant state which, when reactivated, is capable of producing infectious viral particles. These additional reservoirs must be taken into account if we are to one day completely eradicate the virus in patients.
Cécilia Ramirez is drawing on this knowledge of these new tissue reservoirs of the virus to find novel therapeutic solutions. Her objective is to identify existing medicines that could specifically inhibit the production of HIV, from all viral reservoirs, whether lymphocytes or macrophages.
But the ideal would be to block HIV infection completely. Some people are capable of this. Despite coming into frequent contact with the virus, they are never infected. How?
Part of the response is explained by the presence of protective IgA antibodies that target the virus in their genital mucosa. Daniela Tudor, along with Inès Sahnoune and Andrea Calamarte-Cottignies, is studying the multiple antiviral activities of these antibodies. Like this, the team has described many protective mechanisms involving these IgAs and has even developed a mucosal vaccine. Reproducing the protection observed in resistant women, the vaccine provides full protection against genital infection in monkeys and has given positive results in phase 1 clinical trials.
Studying the infectious process provides other preventive solutions. Yonatan Ganor has discovered a molecule, the CGRP neuropeptide, which is secreted following feelings of warmth, friction or pain, and is capable of blocking the early stages of infection of the foreskin with HIV. The peripheral neurons that innervate the mucous membranes, producing neuropeptides, participate in the immune dialogue that reduces HIV infection. Understanding the antiviral mechanisms involved could have therapeutic implications.
The team’s work is echoed in the fight against other viruses, including SARS-CoV‑2. At the start of the pandemic, Bomsel and her team received samples of blood and mucosa from patients severely affected with COVID in order to identify immune factors or markers predictive of severe forms and death. What they found was that these patients develop mucosal immunity. However, the mucosal antibodies that they develop, although persisting for quite a long time, are not neutralizing. They are even considered to have harmful functions.
Today, the issue is changing, with 8% of SARS-CoV‑2‑infected patients who go on to develop long COVID. The latency of the virus in the cells is somewhat unexpected and the team is investigating, as with HIV, the presence of viral reservoirs that could explain the persistence of coronavirus in the body and become new therapeutic targets.
Morgane Bomsel is leader of the Mucosal Entry of HIV and Mucosal Immunity team at Institut Cochin in Paris (unit 1016 Inserm/CNRS/Paris Cité University).