Professor, Leibniz Institute of Virology
Sex differences in HIV-1 pathogenesis
Immune responses differ between females and males, with consequences for infectious diseases and autoimmune diseases. In my presentation, I will review sex differences in HIV-1 pathogenesis, and present novel data on the role of genes encoded by the X chromosome and steroid hormones in mediating sex differences in immune responses against HIV-1
Research Director at CNRS. Head of the laboratory of Molecular Virology. Institute of Human Genetics. Montpellier. France
The journey of HIV-1 DNA: From its synthesis to integration into the host genome
During retroviral infection, viral genomic RNA is used to synthesize a histone-free, viral DNA copy. vDNA will ultimately integrate into the host genome to ensure its maintenance and expression. This course of the viral genome is undermined by traps set up by the host cell. We will discuss the role of viral proteins present in virions and host factors associated with neosynthesized viral DNA in the escape from intracellular immunity.
DR1 au CNRS, head of the team: Mucosal entry of HI and Mucosal Imunity, Institut Cochin
Non-T cell tissue niches for HIV reservoirs in human macrophages and megakaryocytes and their cross talk
Despite efficient combined antiretroviral therapy (cART), HIV-1 eradication is hampered by viral persistence in cell reservoirs. Genetic analyses of the virus rebounding upon cART interruption showed that HIV reservoirs not only establish in circulatory CD4+ T-cells but also in non T-cells in tissues. The nature of these tissue reservoirs and mechanisms of persistence remained unclear, although likely candidates were tissue macrophages and megakaryocytes that are both infected by the virus upon early infection.
Challenging the paradigm of a CD4+ T-cell only reservoir, we established that in individual under suppressive cART, resident mucosal macrophages harbor viral DNA, RNA and viral particles stored in a virus containing compartments (VCCs) characteristic of myeloid cells. Moreover, these persistently infected macrophages form a replication competent reservoir from which viral latency could be reversed upon TLR4 activation. We next evaluated the implication of macrophage immunometabolic pathways in HIV-1 persistence. We demonstrated that this transcriptionally active reservoir resides in M4-polarized macrophages with and inflammatory IL-1R+ S100A8+ MMP7+ phenotype prone to glycolysis. The alarmin S100A8, an endogenous TLR4-ligand produced by M4-macrophages and implicated in “ sterile” inflammation reactivated infectious virus production and release from these macrophage reservoirs in vitro in a process that metabolically depends on glycolysis.
We next revealed that bone marrow megakaryocytes, at least in cART-suppressed patients with sustain low CD4+T cells counts, formed an additional reservoir with integrated viral DNA. In these patients, megakaryocyte reservoirs produced platelets sheltering infectious HIV-1. In vitro, patient platelets harboring HIV propagated the virus to macrophages, in a process that could be prevented with the drug abciximab, an anti–integrin aIIb/b3 Fab.
Altogether, inflammatory M4-macrophages constitute a major tissue reservoir of replication-competent HIV-1, which reactivate viral production upon S100A8-mediated autocrine/paracrine glycolytic stimulation. Furthermore, our study suggests that platelets may be transient carriers of HIV-1 and may provide an alternative pathway for HIV-1 dissemination in HIV-1-infected individuals on cART with viral suppression. Finally, platelets are known to be the major carrier of platelet factor 4 (PF4), the cytokine polarizing macrophages to the M4-subtype and to contain the alarmin S100A8, which is synthesized by megakaryocytes in addition to myeloid cells. We therefore suggest that HIV infected platelets establishes a cross talk between the two reservoirs in megakaryocyte and macrophages. Capture of infected platelets with tissue macrophages together with local release of platelet PF4 and the alarmin S100A8 may contribute to M4-polarization, and sustain the long lasting reservoir in macrophages. These HIV-1 persistence pathways needs to be targeted in future HIV eradication strategies.
Yeargan-Bate Professor of Medicine, Microbiology and Epidemiology
Treatment of HIV for Prevention: Reaching Full Potential
The Next Frontier: Breakthroughs in HIV Post-Nuclear Entry Research
Herman and Louise Smith Distinguished Professor of Medicine
Novel antiretroviral therapies for people with HIV and why we need them
Current antiretroviral therapy for people with HIV (PWN) is remarkably effective and reliably safe. Most PWH can be managed with one combination pill each day and even PWH with resistant virus can maintain HIV RNA suppression with once daily therapy. These treatments are not successful in all PWH. Some have highly resistant virus and require new agents that work by new mechanisms. Others struggle to manage oral therapy or are hardly reached by our traditional medical approaches. Alternative antiretroviral that work by novel mechanisms or have characteristic or delivery systems that allow infrequent dosing will help us reach all people with HIV benefiting individual and public health. This talk with explore these new antiretroviral agents, long acting strategies and novel combinations that have entered clinical care or clinical trials.
Trained as a sound engineer, Hugues Fischer has worked for more than thirty years in audiovisual engineering. He has been an Act Up-Paris activist since 1989. Former president of the association (2006-2008), he has provided scientific training on AIDS to many activists and is the author of the guide "AIDS, the basics to understand". He has represented Act Up-Paris in the inter-associations group TRT-5 since 2003. He was appointed a member of the National AIDS and Viral Hepatitis Council in 2015.
Communities and activists: from confrontation to partnership in research
Professor of Medicine, Microbiology and Immunology
Resident microbiota is a major driver of the acquisition and pathogenesis of HIV and EBV
Germ free (GF) mice are the gold standard for exploring microbiota’s role in health and disease. However, many human pathogens do not replicate in mice. We developed GF humanized mice that are systemically reconstituted with human immune cells. Using GF-BLT mice and conventional (CV)-BLT mice colonized with resident microbes, we evaluated microbiota’s role in EBV and HIV (two human-specific pathogens) acquisition, replication, and pathogenesis. Resident microbiota enhanced the establishment of EBV infection and EBV-induced tumorigenesis. Resident microbiota increased mucosal HIV acquisition and replication. Oral and rectal HIV acquisition were 300% and 200% higher in CV-BLT mice, respectively. HIV-RNA levels were up to 34-fold higher in plasma and over 1,000-fold higher in tissues of CV-BLT mice. Thus, resident microbiota are a major driver of the acquisition and pathogenesis of two clinically relevant human-specific pathogens.
Sociologist, Research fellow SESSTIM (Inserm - Aix-Marseille Université - IRD) - ISSPAM
Undoing Risk? Sociological Perspectives on HIV Prevention
For the past 40 years, risk has been at the heart of debates, studies and practices surrounding the AIDS epidemic: whether on an intimate, community, medial or political level. But the paradigms of HIV risk have shifted dramatically in recent decades, with TasP, PrEP, normalization and chronicization... This talk proposes to put into perspective how risk is still a driver and an unthought in social relations, public policy and research. The intervention will be based on a critical reading of some key social science works in the field of prevention and risk perception.
President and CEO of SAMRC
Vaccine evaluation and development in Africa; COVID-19 pandemic lessons
Clinical implementation of HIV discoveries
Senior research fellow
NK cell differentation and viral control in SIV infection models
Laura H. Carnell Professor and Chair
CRISPR for the elimination of HIV-1
The application of the CRISPR gene editing approach to animal models results in the removal of the designated integrated proviral DNA from host DNA with no adverse effects on the health of the treated animal. Inactivation of HIV-1 in humanized mice by CRISPR along with editing of CCR5, a co-receptor for HIV-1, in the host genome results in suppression of viral rebound in more than 50% of experimental animals. These observations support the notion that HIV-1 cure by CRISPR is possible.
Director of Research, IRD
Transforming effective innovations into efficient interventions: contributions from social and and implementation sciences
L'histoire de la lutte contre le sida a été marquée par le développement d'innovations scientifiques et biomédicales majeures : antirétroviraux, tests rapides de dépistage, prophylaxie préexposition... Cependant, ces innovations ont souvent été insuffisantes, à elles seules, pour infléchir durablement l’épidémie. Il a été essentiel d'innover également en matière de financements, d'organisation des services et des soins, d'approches "hors les murs", de droits humains, de prise en compte des spécificités des populations les plus vulnérables...
Une innovation efficace sera inefficiente si elle n’est pas adaptée aux contraintes sociales, culturelles, légales auxquelles les populations font face et aux contraintes structurelles, organisationnelles et économiques des systèmes de santé. D'où le besoin d’une véritable science de la mise en œuvre nécessairement interdisciplinaire et intersectorielle.
Team leader at Institut Cochin, Paris/ Research director at INSERM
Molecular conflict between HIV and host restriction factors
Sequencing of the genomes of HIV-1 and HIV-2 following their identification as causative agents of human AIDS revealed an unsuspected genetic complexity. In addition to the gag, pol and env genes, which represent the prototypical retroviral genes, the HIV genomes encode two critical regulatory proteins, tat and rev, as well as a set of « accessory » or « auxiliary » proteins. The latter were soon found dispensable for viral replication, at least in certain in vitro cellular systems. However, the emergence of these auxiliary proteins, which have no counterparts in other retroviral groups, strongly suggested that they fulfill specific needs of HIVs in the context of natural infection. Accordingly, they have stimulated intense investigation for 40 years. The current view strikingly illustrates the ever-lasting molecular conflict between viruses and their host cells. Indeed, HIV auxiliary proteins principal function is to rid the virus of host factors that compromise its replication: the so-called restriction factors. These host factors are not passive barriers but rather intrinsic antiviral cell defenses acquired during evolution. Here we will focus on one viral auxiliary protein, namely Vpx, which is specific for the HIV-2/SIVsm lineage. We will show how the study of Vpx led to the discovery of prominent host restriction factors, SAMHD1, a dNTP hydrolase, and HUSH, a repressor of HIV gene expression that could contribute to HIV latency. Inactivation of HUSH by Vpx strengthens the idea of HIV latency as a cellular defense mechanism protecting genomic and proteomic integrity.
Professeur de maladies infectieuses à l’Université de paris Cité et chef du service des maladies infectieuses des hopitaux St-Louis et Lariboisière à l’APHP
Past, Present and Future of PrEP
A sustained focus on HIV prevention is required to reach the WHO/UNAIDS Goals of less than 200,000 new HIV-infections by 2030. Pre-exposure prophylaxis (PrEP) is a key element of the combination prevention strategy for HIV, along with anti-retroviral therapy (ART), HIV testing, and condom provision.
First evidence on the efficacy and safety of daily oral pre-exposure prophylaxis (PrEP) with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) for the prevention of HIV infection was published more than a decade ago, but it was only in 2015 following the results of two European studies that the full potential of PrEP was appreciated and led to broad approval by the World Health Organization (WHO). PrEP was gradually scaled up with near 4 million PrEP users in 2023, but PrEP remains largely underused.
There are substantial inequalities and regional variability in its availability and implementation. As a result, overall coverage for people who are at the highest risk is still deficient. In France, a recent study estimated that only 28% of MSM reported the use of PrEP for their last condomless anal intercourse with a casual partner.
The key determinant of PrEP efficacy is medication adherence, which is particularly challenging in daily dosing regimens for some of the most at-risk populations, such as cis and transgender women, young individuals, racial and ethnic minorities, and injecting drug users.
Long-acting agents and extended-release formulations are very promising novel PrEP candidates. Long-acting injectable cabotegravir (CAB-LA) is the first injectable ART approved for HIV PrEP in the USA. CAB-LA has demonstrated safety and superior effectiveness for preventing HIV infection than daily TDF-FTC among MSM, transgender women, and cisgender women when administered as a single 600-mg intramuscular injection every 2 months. Lenacapavir is another long-acting antiretroviral drug, from the new class of HIV capsid inhibitor, which is also being assessed as an injectable PrEP agent, in phase III PrEP trials. LEN-LA can be self-administered in the subcutaneous tissue once every 6 month and has a great potential for PrEP if trials demonstrate effectiveness.
The use of long-acting broadly neutralizing antibodies (bNAbs) is another promising approach to preventing HIV acquisition. Topical agents or microbicides are other alternatives. In 2021, the WHO recommended a monthly dapivirine intravaginal ring for HIV prevention in cis-gender women, based on the results of two phase-III randomized placebo-controlled clinial trials showing a 27% and 35% relative reduction of HIV incidence.
Finally, innovative alternatives for PrEP include new drug delivery systems such as subdermal implants and transdermal devices that could provide continuous protection from HIV over time, and multipurpose prevention technologies, which could deliver prevention for HIV and other STIs, with or without contraception.
Despite the progress made in scaling up PrEP, this prevention strategy has not yet reached its full potential in curtailing the HIV epidemic. At each step of the PrEP care continuum, several barriers persist. A more ambitious and holistic approach is still required to address individual, structural, social, and political barriers. To achieve this goal, specific attention must be given to PrEP awareness and education.
Head of the Humoral Immunology Unit, Institut Pasteur
Human broadly neutralizing antibodies to HIV-1 and beyond
Therapeutic strategies in Africa (TBC)
Associate Professor at Africa Health Research Institute (AHRI)
Using Spatial Biology and Multi-Omics approaches to understand HIV Persistence in tissues
My research seeks to address the major obstacle to HIV cure by identifying means of enhancing immune responses in secondary lymphoid organs (SLO) where HIV hides to evade detection and elimination by the immune system. My presentation will focus on the spatial transcriptomic analysis of HIV infected lymph nodes to better understand molecular mechanisms that contribute to follicular reservoir persistence within SLOs in the face of suppressive antiretroviral therapy. This work will guide the development of new approaches to overcome barriers to HIV eradication in tissues.
Zanvil A Cohn and Ralph M Steinman Professor, The Rockefeller University
Human Antibodies in HIV-1 Therapy
New insights into viral control
Professor, The Scripps Research Institute
Vaccine design to induce broadly neutralizing antibodies against HIV
Head of Virus and Immunity Unit
Breaking Barriers: Exploring Viral Fusion and its Inhibition
Professor of Clinical and Health Psychology, Institute for Global Health, University College London, UK
Don't pass me by - the person at the centre of HIV... (Zoom TBC)
The arrival of HIV signified a dramatic turn in the approach to care, prevention, inclusion and human understanding. As the intricacies of the HIV virus were explored, as testing and treatments came on board, as humanity recorded transmission pathways, the biomedical phenomenon of HIV opened up the burning need for holistic approaches and shone a light on the importance of social science to understand every step of the pathway. This talk will track the use of evidence based social science to understand both the impact of HIV and possible solution pathways in the management and response. The focus will concentrate on women and children as an example of groups who are often overlooked, misunderstood and underserved.
Distinguished Professor and Samuels Chair of Biochemistry, University of Utah, Salt Lake City, USA
Structure and function of the HIV capsid
The HIV capsid organizes the viral replication complex, protects the viral nucleic acids from innate immune surveillance, and targets the virus to the nucleus for integration. The capsid is also the target for Gilead’s very potent and long-lasting anti-HIV drug, Lenacapavir/Sunlenca®. I will review the advances in our understanding of viral capsid structures and functions, and how this understanding is being leveraged to create new therapeutic opportunities.
Associate Professor in Medicine, Harvard Medical School, Core Member, Ragon Institute of MGH, MIT and Harvard
HIV-1 Cure informed by Elite Controllers
HIV-1 elite controllers arguably represent the closest possible approximation to a cure of HIV-1 infection. Two possible types of an HIV-1 cure have been recognized thus far: a virological cure with the elimination of all HIV-infected cells that encode for replication-competent HIV, and a functional cure, characterized by enrichment of intact proviruses within heterochromatin positions associated with deep latency. Both forms of a cure may result from immune-mediated clearance of HIV-1 reservoir cells harboring intact proviruses in accessible chromatin locations. Effective immune responses in people living with HIV-1 may, after extended periods of antiretroviral therapy, also be able to induce viral reservoir profiles dominated by intact proviruses in heterochromatin locations; such an atypical reservoir profile, might, in rare cases, contribute to drug-free control of HIV after treatment interruption. Identifying immune mechanisms that can drive selection of intact proviruses in deep latency will represent an important research priority for future studies.