Pierre Delobel

The characteristics of HIV-1 envelope glycoproteins (Env) that initiate infection remain incompletely understood. In the primary HIV infection (PHI) stage, Envs using CCR5 as entry coreceptor (R5-tropic Envs) are much more frequent than those using CXCR4, alone or in addition to CCR5 (X4 or R5X4 Envs). However, a comprehensive analysis of the genetic identity and functional properties of CXCR4-using Envs during PHI is lacking to attest whether they are less transmissible than R5 Envs. Here, Env populations in the plasma of 22 recently infected individuals with R5 or CXCR4-using viruses were characterized by single-genome amplification. Mathematical modeling of HIV evolution, phylogenetic analyses, and viral quasi-species complexity indices showed that infection with CXCR4-using viruses is most often initiated by one, occasionally two variants, similar to R5 viruses. After transmission, the diversity and complexity of CXCR4-using and R5 Env populations increase similarly during PHI, with mutations accumulating in preferential regions of the gp120 portion of Env, but not in gp41. Both Env types also shared similar traits influencing viral transmission (variable loop length, N-glycosylations) and T-cell– but non-macrophage–tropism. However, CXCR4-using Envs exhibited specific sensitivity profiles to neutralization by soluble CD4 and broadly neutralizing antibodies (bNAbs), suggesting differences in epitope exposure and conformational dynamics compared to R5 Envs. These results, therefore, indicate that CXCR4-using viruses are equipped to initiate infection and, like R5 viruses, undergo a genetic bottleneck during transmission. The specific antigenicity of transmitted CXCR4-using Envs could help improve protocols using bNAbs for passive immunization and HIV vaccine development. IMPORTANCE: Transmitted/founder (T/F) viruses are predominantly R5-tropic, and only on rare occasions have T/F viruses that use CXCR4 been reported in the literature. Consistently, R5 viruses account for over 90% of the viruses present during primary HIV infection (PHI). However, it remains unclear whether CXCR4-using Envs, unlike R5 Envs, lack key properties for virus transmission and/or persistence in the new host. Here, we found that transmitted CXCR4-using Envs shared with R5 Envs common genetic and functional determinants, demonstrating their potential to transmit infection. So, the low prevalence of CXCR4-using viruses among donors probably explains why they are infrequently transmitted. As with R5 viruses, a genetic bottleneck occurs during transmission of CXCR4-using viruses, suggesting that the barriers determining this bottleneck are independent of viral tropism. Remarkably, transmitted CXCR4-using Envs exhibit distinct antigenic properties compared to R5 Envs, which could be leveraged to improve broadly neutralizing antibody-based preventive and therapeutic vaccine strategies.

ID2 expression is typically associated with promoting effector differentiation in CD8⁺ T cells. Here, we show that ID2 upregulation instead characterizes the optimal memory CD8⁺ T cell response in individuals who naturally maintain durable control of HIV-1 without therapy. We further identify a subset of memory CD8+ T cells co-expressing the transcription regulators TCF1 and ID2 that combine stemness with broad effector functions. These TCF1+ID2+ cells exhibit high proliferative capacity, robust cytokine production, and restrained expression of exhaustion markers, enabling sustained responses upon repeated antigen stimulation. They constitute the predominant virus-specific memory CD8+ T cell population in naturally controlled CMV, HIV-1, and SIV infections. Our findings reveal a poised memory state that balances effector and survival programs, suggesting that TCF1+ID2+ memory CD8+ T cells play a central role in maintaining durable antiviral immunity during persistent infections.

Background: Doravirine, the most recent NNRTI, may advantageously replace etravirine in virally suppressed PWH. We evaluated the tolerance and efficacy of doravirine-based ART following a switch from etravirine-based ART. Methods: SWEED is a national, multicentre, retrospective, observational study including adults with HIV-1 and plasma viral load (pVL) <50 copies/mL on etravirine-based ART, who switched to doravirine-based ART (same number of associated drugs) from 09/01/2019 in 10 French hospitals. The primary outcome was virological failure (VF: confirmed pVL ≥50 copies/mL or single pVL ≥50 with ART change) at week 48 (W48). Secondary outcomes included rates of strategy success (pVL <50 copies/mL with no ART change) and treatment discontinuations due to side effects, and changes in CD4 counts and weight. Results: Among 109 participants (79% men; median age 59 years), median ART duration was 25 years, with 13 years of sustained viral suppression. Prior NNRTI failure was documented in 41% of participants, and 46% had resistance mutations to at least one NNRTI. ART consisted of 2-drug (53%) and 3-drug (42%) combinations. Median follow-up was 30 months. One VF occurred by W48 (0.9%, 95%CI: 0.0–5.0); viral suppression was regained without ART change. Four patients discontinued doravirine-based ART due to adverse events; strategy success rate was 91.7% (95% CI: 84.9–96.2) at W48. No significant changes in CD4 counts and weight were observed. Conclusion: Doravirine-based ART maintained virological suppression in PWH switching from etravirine-based ART, even in presence of prior NNRTI resistance. Its once-daily dosing, favourable safety profile, and minimal drug interactions support its use in long-term ART strategies.

Purpose: This narrative review aims to provide an overview of current knowledge on mpox, emphasizing updated epidemiology and recent advances in treatment and prevention strategies, in light of the latest outbreaks. Methods: We searched PubMed and Google Scholar for publications on ‘Mpox’ and ‘Monkeypox’ up to June 5, 2025. Grey literature from governmental and health agencies was also accessed for outbreak reports and guidelines where published evidence was unavailable. Results: Recent outbreaks have redefined mpox epidemiology. Whereas previous regional outbreaks were mainly driven by zoonotic spillover with limited household transmission and often affecting children, more recent outbreaks have involved sustained human-to-human transmission. Such transmission has occurred among men who have sex with men for clade IIb and within heterosexual networks for clade Ib outbreaks, and more recently clade Ia outbreaks, primarily through sexual contact. Clinical features have also shifted toward more localized lesions, prominently in the anogenital area. While mpox is usually self-limited, severe cases may occur in pregnant women, young children, and immunocompromised individuals. Mpox management primarily relies on supportive care. In patients with severe mpox, or at risk of, tecovirimat was widely recognized as the first-line therapy, although it has failed to demonstrate its effectiveness in recent randomized controlled trials. The Modified Vaccinia Ankara vaccine (two-dose regimen) has shown a favorable safety profile and promising efficacy data in preventing clade IIb mpox, including immunocompromised individuals. Conclusion: Mpox has transitioned from a neglected zoonosis to a re-emerging global health threat. Sustained surveillance, robust and targeted public health interventions, and equitable access to diagnostics, vaccines, and antiviral treatments are critical to managing potential future mpox outbreaks.

Vδ₁ γδ T cells are key players in innate and adaptive immunity, particularly at mucosal interfaces such as the gut. An increase in circulating Vδ₁ cells has long been observed in people with HIV-1, but remains poorly understood. We performed a comprehensive characterization of Vδ₁ T cells in blood and duodenal intra-epithelial lymphocytes, obtained from endoscopic mucosal biopsies of 15 people with HIV-1 on antiretroviral therapy and 15 HIV-seronegative controls, in a substudy of the ANRS EP61 GALT study (NCT02906137). We deciphered the phenotype, functional profile, single-cell transcriptome and repertoire of Vδ₁ cells and unraveled their relationships with the possible triggers involved, in particular CMV and microbiota. We also assessed whether Vδ₁ T cells may play a role in controlling the HIV-1 reservoir. Vδ₁ T cells were mainly terminally differentiated effectors that clonally expanded in the blood with some trafficking with the gut of people with HIV-1. Most expressed CX3CR1 and displayed a highly cytotoxic profile, but low cytokine production, supported by a transcriptomic shift towards enhanced effector lymphocytes. This expansion was associated with CMV status and markers of occult replication, but also with changes in the duodenal and blood-translocated microbiota. Cytotoxic, but not IFN-γ-producing, Vδ₁ T cells were negatively associated with cell-associated HIV-1 RNA in both the blood and duodenal compartments. The increase in Vδ1 T cells observed in people with HIV-1 has multiple triggers, particularly CMV and microbiota, and may in turn contribute to the control of the HIV-1 reservoir.

Importance: Infective endocarditis (IE) caused by Staphylococcus aureus is associated with high mortality, approximately 20% to 30%, mostly in the first month, with no improvement in recent decades. Current opinion is that antistaphylococcal penicillin and cefazolin are equally effective in treating methicillin-susceptible S aureus (MSSA) IE, and both are recommended as possible first-line treatments. Most MSSA strains carry the β-lactamase blaZ gene, and some blaZ-positive strains exhibit an inoculum effect, meaning increased minimum inhibitory concentrations at high inoculum. This reduced susceptibility to an antibiotic at high bacterial inoculum may be particularly relevant in IE, where vegetations have very high bacterial densities.Objective: To evaluate the association between phenotypic characteristics of S aureus isolates, β-lactam used, and outcome in patients with MSSA IE.Design, Settings, and Participants: This retrospective case series included MSSA cases treated at 3 French university hospitals between February 2016 and February 2022. The study included patients who had clinical isolates available and had definite or possible S aureus IE that involved native or prosthetic valves. Data were analyzed from July 2023 to June 2024.Main Outcomes and Measures: MSSA isolates were tested for the presence of blaZ and for inoculum effects to cefazolin and oxacillin. The association between first-month mortality and the β-lactam used, the presence of blaZ, and the presence of an inoculum effect to the treatment received was evaluated.Results: This study included 216 patients with MSSA IE (median [IQR] age, 65 [49-73] years; 152 [70.4%] male) who were treated with antistaphylococcal penicillin (139 [64.4%]) or cefazolin (77 [35.6%]). One-month mortality of left-sided IE was 44 of 180 patients (24.4%), with no overall difference between patients treated with antistaphylococcal penicillin or cefazolin. However, 1-month mortality was higher in patients infected with blaZ-positive strains than with blaZ-negative strains (38 of 129 [29.5%] vs 6 of 51 [11.8%]; P = .01), and with strains with an inoculum effect to the β-lactam received than with strains without an inoculum effect (25 of 62 [40.3%] vs 13 of 67 [19.4%]; P = .005). On multivariable analysis, the presence of an inoculum effect was independently associated with first-month mortality (HR, 2.84; 95% CI, 1.28-6.30; P = .01).Conclusions and Relevance: In this case series of MSSA IE, the presence of an inoculum effect to the β-lactam received was a risk factor for death in the first month. Phenotyping MSSA isolates for inoculum effect may guide β-lactam choice and improve outcomes.

The persistence of latently infected cells prevents a cure of HIV. The intestinal mucosa contains numerous target cells, and high levels of HIV-1 DNA persist in this compartment under ART. While CD4⁺ T cells are the best characterized reservoir of HIV-1, the role of long-lived intestinal macrophages in HIV-1 persistence on ART remains controversial. We collected duodenal and colonic biopsies from 12 people living with HIV (PLWH) on suppressive ART, enrolled in the ARNS EP61 GALT study. Total, integrated, intact and defective HIV-1 proviruses were quantified from sorted T cells and monocytes/macrophages. HIV-1 env quasispecies were analyzed by single-molecule next-generation sequencing and env-pseudotyped viruses were constructed to assess macrophage versus T-tropism. Total HIV-1 DNA levels in intestinal T cells were significantly higher than those in monocytes/macrophages (P<0.0001). Unintegrated HIV-1 DNA was detected in one-third of T-cell and monocyte/macrophage-positive samples. Intact HIV-1 proviruses were detected using the intact proviral DNA assay in 4/16 T-cell samples and 1/6 monocyte/macrophage samples with detectable HIV-1 DNA. HIV-1 sequences were compartmentalized between intestinal monocytes/macrophages and T cells in some subjects. Phenotypic analysis of pseudotyped viruses expressing HIV-1 envelopes from colonic monocytes/macrophages revealed T-tropism rather than M-tropism. Our results show that monocytes/macrophages from the intestinal mucosa of PLWH on ART can contain HIV-1 DNA, including intact or unintegrated forms, but at much lower levels than those found in T cells, and with some compartmentalization although they do not exhibit a specific macrophage tropism, raising the question of the mechanisms of infection involved.

Background Immune checkpoint inhibitors (ICIs) have been a major advance in cancer management. However, we still lack prospective real-world data regarding their usage in people with HIV infection (PWH). Methods The ANRS CO24 OncoVIHAC study (NCT03354936) is an ongoing prospective observational cohort study in France of PWH with cancer treated with ICI. We assessed the incidence of grade ≥3 immune-related adverse events (irAEs). All grade ≥3 irAEs were reviewed by an event review. Results Between January 17, 2018, and December 05, 2023, 150 participants were recruited from 33 sites and 140 were included in this analysis. At the data cut-off date of December 05, 2023, the median follow-up was 9.2 months (IQR: 3.9–18.3), with a total of 126.2 person-years. Median age was 59 years (IQR: 54–64) and 111 (79.3%) were men. Median time since HIV diagnosis was 25 years (12–31), the median duration on antiretroviral (ARV) was 19.5 years (7.7–25.4), and the CD4 nadir was 117/µL (51–240). ICI regimens comprised anti-programmed cell death protein-1 (PD-1) for 111 (79.3%) participants, anti-programmed death-ligand 1 for 25 (17.9%), a combination of anti-PD-1 and anti-cytotoxic T-lymphocyte associated protein 4 for 3 (2.1%), and anti-PD-1 along with anti-vascular endothelial growth factor receptor for 1 (0.7%). The most frequent cancers were lung (n=65), head/neck (n=15), melanoma (n=12), liver (n=11) and Hodgkin’s lymphoma (n=9). During follow-up, a total of 34 grade ≥3 irAEs occurred in 20 participants, leading to an incidence rate of 26.9 per 100 person-years. The Kaplan-Meier estimates of the proportion of participants with at least one episode of grade ≥3 irAEs were 13.8% at 6 months, 15.0% at 12 months and 18.7% at 18 months. One treatment-related death due to myocarditis was reported (0.7%). Multivariable analysis of cumulative incidence showed that participants with time since HIV diagnosis >17 years (incidence rate ratio (IRR)=4.66, p=0.002), with CD4Conclusion This study showed that the incidence of a first episode of grade ≥3 irAE was 15.0% (95% CI: 9.6% to 22.9%) at 1 year and the cumulative incidence of all severe irAE episodes was 26.9 per 100 person-years. Low CD4 count, positive CMV serology, history of cancer surgery and a longer time since HIV diagnosis were associated with the occurrence of severe irAEs.

Purpose: Immunocompromised patients have a potentially increased risk for progression to severe COVID-19 and prolonged replication of SARS-CoV-2. This post hoc analysis examined outcomes among immunocompromised participants in the MOVe-OUT trial. Methods: In phase 3 of MOVe-OUT, non-hospitalized at-risk adults with mild-to-moderate COVID-19 were randomized to receive molnupiravir 800 mg or placebo twice daily for 5 days. Immunocompromised participants were identified based on prior/concomitant medications and/or medical history. All-cause hospitalization/death, adverse events, SARS-CoV-2 titers, infectivity, and RNA sequences were compared between immunocompromised participants who received molnupiravir or placebo and with non-immunocompromised participants. Results: Fifty-five of 1408 participants were considered immunocompromised. Compared to placebo, fewer molnupiravir-treated immunocompromised participants were hospitalized/died through Day 29 (22.6% [7/31] vs. 8.3% [2/24]), with fewer adverse events (45.2% [14/31] vs. 25.0% [6/24]). A larger mean change from baseline in SARS-CoV-2 RNA was observed with molnupiravir compared to placebo in non-immunocompromised participants (least squares mean [LSM] difference Day 5: – 0.31, 95% confidence interval [CI] – 0.47 to – 0.15), while the mean change was comparable between treatment groups in immunocompromised participants (LSM difference Day 5: 0.23, 95% CI – 0.71 to 1.17). Molnupiravir treatment was associated with increased clearance of infectious virus. Increased errors in viral nucleotide sequences in post-baseline samples compared to placebo support molnupiravir’s mechanism of action and were not associated with observation of novel treatment-emergent amino acid substitutions in immunocompromised participants. Conclusion: Although the study population was small, these data suggest that molnupiravir treatment for mild-to-moderate COVID-19 in non-hospitalized immunocompromised adults is efficacious and safe and quickly reduces infectious SARS-CoV-2. ClinicalTrials.gov Registration Number: NCT04575597.