Basic HIV research advances with the development of new technologies and so is, by definition, open to innovation and creativity. The aim of basic research is to unveil the mechanisms of infection by HIV and by simian immunodeficiency virus. More specifically, it focuses on host-virus interactions in HIV infections, in molecular, cellular, virological, immunological, and pathophysiological terms. In this way, the hope is that research will generate scientific knowledge and a firm basis for the design of preventive, prophylactic, and therapeutic approaches to AIDS and other illnesses.
One of today’s major scientific challenges is to understand the mechanisms that enable the persistence of HIV infection, which prevents treatment discontinuation and curative treatment of patients.
Characterization of viral reservoirs
Memory CD4 cells, which harbor latent HIV, have been characterized by numerous teams as the main reservoirs of HIV in patients treated at the chronic phases of the infection.
Recent and ongoing studies at the ANRS show that reservoirs of HIV are also to be found in other cell types in patients who control viral replication spontaneously or after treatment (Codex cohort). Other studies under way are intended to establish the profile of infected cells, using a so-called “unbiased” or “omics” approach, so as to examine simultaneously several parameters, such as the activation state of infected cells, their metabolic activity, cell cycle stages, and the membrane markers associated with infected populations.
Identification of a marker for specific screening for viral reservoirs
The identification of specific markers of viral reservoirs to enable their selective elimination would have a major societal impact.
A French team has developed an original experimental system for the study of the HIV latency in vitro. This has led to the identification of a membrane protein present exclusively in T cells latently infected by HIV. This team is currently using several approaches to confirm these results in animals and in humans. Among others, the aim is to create tools to target and eliminate viral reservoirs via an immunotherapeutic approach.
Cell death and elimination of viral reservoirs
In research seeking curative treatment of HIV infection, studies are focused on reversing viral latency and on the specific targeting and elimination of viral reservoirs.
In this sense, several ANRS teams are studying the mechanisms of "cell death" (apoptosis, autophagy) following infection by HIV or simian immunodeficiency virus. For example, preclinical trials are currently studying the effect on the reservoirs of cell death pathway inhibitors (of caspases and of the TRAIL pathway).
Immunological control of infection: spin-offs for research on infection prevention and control
Numerous ongoing studies relate to the anti-HIV immunological response in infected individuals who control viral replication (Codex and ANRS CO5 HIV-2 cohorts), so-called "elite controllers" or long-term nonprogressors. The aim is to determine the immunological correlates of protection. New technologies bring greater depth to studies and now cell analysis and sorting can be done on the scale of a single cell.
Based on these new methods, one study has characterized CD4 cells, which have special T cell receptors able to detect a minute quantity of virus. This study is currently investigating the possibility of inducing this property in the cells of patients who are not "controllers," resulting perhaps in spin-offs for vaccine research.
A study in cohort ANRS CO5 HIV-2 has recently shown that CD8 cells from long-term nonprogressors infected by HIV-2 have an increased capacity to suppress viral production. This depends on the capacity of such nonprogressors to preserve certain functions of their immune system cells, and this is currently under study.
Reservoirs and tissue determinants of HIV persistence
One characteristic of immune system cells is their capacity to circulate in the body and to differentiate in lymph organs before entering tissues. Depending on the tissue, HIV-infected cells receive signals and stimuli that affect their state of activation and their capacity to produce the virus. A major question is whether or not, in certain tissues, infected cells are protected from the effector cells of the immune system or inaccessible to drugs or both. These tissues constitute sanctuaries where the virus persists and can replicate.
For example, research on the role of macrophages in HIV pathogenesis has conventionally been done in vitro, but is moving towards ex vivo models in order to explore the contribution of macrophages to viral persistence.
ANRS RHIVIERA and p-VISCONTI
ANRS EP47 VISCONTI, a study supported and promoted by the ANRS, was conducted in adult patients who still controlled their infection more than seven years after treatment discontinuation. These patients, who had a symptomatic primary infection with a high viral load, were treated in the first weeks of their infection. In terms of research, these results are particularly important in seeking to eradicate HIV or at least to achieve stable and lasting control of the infection in the absence of antiretroviral treatment.
The VISCONTI study led to the creation of ANRS RHIVIERA (Remission of HIV Infection ERA), a multidisciplinary consortium of researchers tasked with developing new strategies and tools to achieve remission in HIV-infected patients. This consortium is currently working on numerous projects.
While HIV hijacks cellular machinery for its replication, some cellular proteins directly promote the arrest, slowing, or restriction of viral replication. These proteins, some of which are induced by interferons, are called restriction factors. Lentiviruses, like HIV and simian immunodeficiency virus, have genes that enable them to oppose restriction factors, thereby gaining an evolutionary advantage.
Several ANRS teams are using structural, cellular, and molecular studies of cellular restriction factors, like SamHD1, IFITM, and tetherin, with a view to using their capacity to restrict viral replication for therapeutic purposes.
Other early interactions between viral and cellular molecules underpin the body’s detection of the virus. This recognition triggers the first non-specific responses to infection, such as production of interferons and of inflammatory cytokines.
The complex role of interferons in HIV infection has yet to be elucidated. Interferons have antiviral activity, but are also involved in the inflammation and generalized cell activation that characterize infections. Transcriptomics research in nonpathogenic simian models show that inflammation is controlled. Ongoing studies in animals and others in humans are seeking to shed light on the mechanisms underlying this control of inflammation.
HIV is essentially transmitted sexually, and to devise new prevention strategies it is necessary to understand the first steps of viral entry into mucosal membranes.
Current work in vitro using models of human explants and in vivo in simian models is aimed at elucidating the mechanisms of viral transmission, but also the potential role of the microbiota associated with genital mucosa.
In the context of setting up pre-exposure prophylaxis, the ANRS is encouraging translational research on the control of infection in non-infected exposed individuals, in particular studies on mucosal immunity.
The recent identification of human monoclonal antibodies that broadly neutralize HIV and have protective or even therapeutic potential has renewed interest in this subject and may lead to development of an anti-HIV vaccine that induces protective immunity.
ANRS-sponsored work seeks to shed light on the neutralizing coevolution of HIV and immune response antibodies during infection, in both individuals and populations, to identify the capacity of antibodies to prevent cell-to-cell transmission of the virus, and to see how the effector functions of antibodies protect against infection or its progression. Some teams are using knowledge acquired in this field to generate immunogens able to induce protective humoral immunity, whether systemic or mucosal.