Matthieu Perreau

Neurocognitive impairments (NCI) affect up to 50% of persons living with HIV (PLWH), even under anti-retroviral therapy. Evidence suggests that HIV-1 genotypes at least in part contribute to NCI, but most studies considered composite scores and did not examine specific neurocognitive domains. We considered neurocognitive domains assessed in the Neurocognitive Assessment in the Metabolic and Ageing Cohort, a sub study of the Swiss HIV Cohort Study (SHCS), and determined associations with HIV-1 residues, detected by full-length genome sequencing, previously linked to self-reported neurocognitive complaints (SRNC) in the SHCS, using linear regression. Additionally, we determined the heritability with Brownian motion- and mixed models based on viral pol phylogenies. In 192 out of 981 PLWH with full-length sequences, among the top residue variants identified, Env641E and Rev18I had been previously associated with SRNC. Respectively, of identified residue variants, point estimates correlated highly with previous SRNC-estimates from the SHCS for sensory skills (r = −0.71, P < 0.0001) and speed of processing (r = −0.71, P < 0.0001). Heritability estimates in 981 PLWH were significant for sensory skills [25.9%, 95% confidence interval (CI) 5.5–44.6%], motor skills (24.3%, CI 3.7–43.3%), and speed of processing (23.5%, CI 5.2–40.7%). Our findings support prior observations regarding SRNC-associated viral residues and confirm the relevance of the infecting HIV-1 strains for neurocognitive performances.

Background: Studies in Switzerland and other settings have reported minimal pretreatment integrase strand transfer inhibitor (INSTI) resistance, but many were conducted before widespread use of INSTIs or are limited regarding data availability and representativeness. Consequently, many questions remain regarding the transmissibility of INSTI drug resistance mutations (DRMs). Methods: In sequences predating antiretroviral therapy (ART) initiation collected in the Swiss HIV Cohort Study (SHCS) resistance database, we assessed INSTI DRMs using the Stanford HIV database algorithm. We use bayesian regression models to assess INSTI DRM trends, as well as epidemiological clustering. Models are adjusted for age, sex, HIV subtype, and time as a spline, with random effects for the SHCS center of registration and the sequencing laboratory. Results: In total, 3704 SHCS participants had an integrase sequence before ART initiation; 213 (5.8%) had INSTI DRMs, including 11 (0.3%) with major INSTI DRMs. The most common DRMs were the polymorphic accessory INSTI DRMs E157Q, T97A, and L74M. There was no change in the probability of detecting INSTI DRM(s) over the past 3 decades. Epidemiological clustering was similar between individuals with or without pre-ART INSTI DRMs; however, the clusters they formed were smaller, particularly before 2010. Conclusions: This study demonstrates that in Switzerland pre-ART INSTI DRMs are very rare, despite INSTIs being used for more than 10 years. In cases where pre-ART INSTI DRMs are detected, information on the context in which they emerged is rarely available, highlighting the need for continued genetic surveillance, particularly in the face of increasing numbers of individuals with INSTI resistance globally.

Background/Objectives: Sarcoidosis is a granulomatous disease with no widely accepted circulating biomarkers for routine diagnostics. Soluble CD14 (sCD14) and lipopolysaccharide-binding protein (LBP), identified through extracellular vesicle proteomics, have been proposed as candidates. We aimed to compare the diagnostic accuracy of serum sCD14 and LBP with the established biomarker soluble interleukin-2 receptor alpha chain (sCD25). Methods: A matched case–control study included 46 newly diagnosed, untreated sarcoidosis patients and 46 age- and sex-matched healthy controls. Serum sCD14, sCD25, and LBP were quantified by ELISA. BMI was included as a covariate in multivariable logistic regression. Diagnostic performance was evaluated by ROC analysis and stepwise AIC model selection. Longitudinal biomarker dynamics were assessed in 32 patients under treatment. Results: sCD25 demonstrated superior diagnostic discrimination (AUC 0.92, 95% CI 0.87–0.98), compared with LBP (AUC 0.71, 95% CI 0.60–0.82) and sCD14 (AUC 0.61, 95% CI 0.49–0.73). In multivariate analysis, only sCD25 (OR per +100 pg/mL: 1.53; p < 0.001) remained an independent predictor of sarcoidosis. Neither LBP nor sCD14 improved model fit. All biomarkers significantly decreased following therapy. Conclusions: Among routinely measurable serum markers, sCD25 outperformed sCD14 and LBP in sarcoidosis diagnosis. Further studies should explore immunometabolic interactions to refine diagnostic algorithms.

Purpose of review: The existence of HIV controllers offers the possibility of identifying specific immune-virological attributes associated with the control of HIV replication, possibly guiding the development of immunological interventions to achieve a functional cure. In the past few years, pioneering studies focused on the study of viral reservoir and immune responses in lymphoid tissues. In the present review, we propose to summarize their findings. Recent findings: The mechanisms of HIV control in tissues may present peculiar features. Despite efficient viral suppression in vitro , HIV-specific CD8 T cells from lymphoid tissues express lower levels of the classical cytotoxic molecules (Granzyme B and Perforin) directly ex vivo , suggesting that alternative mechanism(s) may operate in these compartments. Interestingly, tissue-resident CD8 T cells from multiple tissues express an array of alternative granzymes, whose contribution to the control of HIV replication remains to be established. NK cells also display peculiar features in lymphoid tissues, including lower levels of classical cytotoxic molecules and increased expression of CXCR5, highlighting the complexity of tissue-specific immunity in the context of HIV. Summary: The immunological mechanisms associated with the control of HIV replication in tissues remain to be fully identified and may involve multiple mediators acting through distinct mechanisms. Recent evidence suggests that the control of HIV replication in lymphoid tissues probably depends on an appropriate positioning of effector cells in the tissue microenvironment, and may be mediated by different mechanisms depending on the levels of viral production and the body compartment.

Elite controllers (ECs) maintain undetectable levels of plasma viremia in the absence of treatment, but small reservoirs of replication-competent proviruses persist in the vast majority of these persons. We longitudinally studied paired blood and inguinal lymph node samples (LNMC) from 2 ECs to better characterize distinguishing features of viral reservoir cell dynamics in ECs. In both participants, we observed a 7- to 10-fold lower frequency of intact proviruses in LNMC samples relative to reservoir cells circulating in blood. The landscape of intact proviruses in both tissue compartments was dominated by shared large clones that were frequently integrated in noncoding DNA regions, but the frequency and diversity of intact proviruses was more limited in LNMCs. Of note, over 9–10 years of longitudinal follow-up, a 3- to 18-fold reduction of intact proviruses was observed. Together, these data support the hypothesis that viral reservoirs in EC blood and lymphoid tissues are under strong, likely immune-mediated selection pressure.

The effect of helminthiasis on host immunity is a neglected area of research, particularly in tuberculosis (TB) infection. This study aimed to evaluate the effect of helminthiasis on immunological and haematological parameters in newly diagnosed TB patients in Bobo-Dioulasso. After all biological analyses, we formed three subpopulations: group 1 (n = 82), as control, were participants without helminthic or Mycobacterium tuberculosis complex infection (Mtb−/Helm−), group 2 (n = 73) were TB patients without helminthic infection (Mtb+/Helm−), and group 3 (n = 22) were TB patients with helminthic infection (Mtb+/Helm+). The proportion of helminth coinfection was 23.16% (22/95) in TB patients, and Schistosoma mansoni infection was found in 77.3% (17/22) cases of helminthiasis observed in this study. A low CD4 T cell count and a low CD4:CD8 ratio were significantly associated with concomitant infection with helminths and the Mtb complex (Mtb+/Helm+) compared to the other groups (p < 0.05). However, there was no statistically significant difference in the CD8 median among the three participating groups (p > 0.05). Lymphopenia, monocytosis, thrombocytosis, and hypochromic microcytic anaemia were the haematological defects observed in the Mtb+/Helm+ and Mtb+/Helm− patients. Exploring these types of immune–haematological biomarkers would be a valuable aid in diagnosing and a better follow-up and monitoring of the tuberculosis–helminthiasis coinfection.

Purpose of review: To underline the complexity and the heterogeneity of the HIV reservoir. Recent findings: While lymphoid tissues (spleen, lymph nodes, gut-associated lymphoid tissue) harbor specific subsets of specialized CD4⁺ T cells enriched in HIV-infected cells, non-CD4⁺ T cell reservoirs such as tissue-resident macrophages and dendritic cells have also been implicated to contribute to viral persistence. Moreover, studies have applied highly sensitive tools to detect transcriptional activity within HIV-infected cells during prolonged ART and revealed a broader spectrum of transcriptional activity for proviruses than previously thought. Finally, while a combination of factors might be involved in the regulation of HIV persistence within different tissues and remains to be fully elucidated, recent results from autopsy samples of HIV-infected ART suppressed individuals indicate extensive clonality of HIV reservoirs in multiple tissues and suggest that the recirculation of HIV-infected cells and their local expansions in tissues may also contribute to the complexity of the HIV reservoirs in humans. Summary: HIV persistence in blood and multiple tissues despite long-standing and potent therapy is one of the major barriers to a cure. Given that the HIV reservoir is established early and is highly complex based on its composition, viral diversity, tissue distribution, transcriptional activity, replication competence, migration dynamics and proliferative potential across the human body and possible compartmentalization in specific tissues, combinatorial therapeutic approaches are needed that may synergize to target multiple viral reservoirs to achieve a cure for HIV infection.

BACKGROUND: Persistent controllers (PCs) maintain antiretroviral-free HIV-1 control indefinitely over time, while transient controllers (TCs) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir in terms of these phenotypes in order to identify the factors that lead to HIV progression and to open new avenues toward an HIV cure. METHODS: The characterization of HIV-1 reservoir from peripheral blood mononuclear cells was performed using next-generation sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-Seq; MIP-Seq). RESULTS: PCs and TCs, before losing virological control, presented significantly lower total, intact, and defective proviruses compared with those of participants on antiretroviral therapy (ART). No differences were found in total and defective proviruses between PCs and TCs. However, intact provirus levels were lower in PCs compared with TCs; indeed the intact/defective HIV-DNA ratio was significantly higher in TCs. Clonally expanded intact proviruses were found only in PCs and located in centromeric satellite DNA or zinc-finger genes, both associated with heterochromatin features. In contrast, sampled intact proviruses were located in permissive genic euchromatic positions in TCs. CONCLUSIONS: These results suggest the need for, and can give guidance to, the design of future research to identify a distinct proviral landscape that may be associated with the persistent control of HIV-1 without ART. FUNDING: Instituto de Salud Carlos III (FI17/00186, FI19/00083, MV20/00057, PI18/01532, PI19/01127 and PI22/01796), Gilead Fellowships (GLD22/00147). NIH grants AI155171, AI116228, AI078799, HL134539, DA047034, MH134823, amfAR ARCHE and the Bill and Melinda Gates Foundation.

Patients admitted to the intensive care unit (ICU) often experience endotoxemia, nosocomial infections and sepsis. Polymorphonuclear and monocytic myeloid-derived suppressor cells (PMN-MDSCs and M-MDSCs) can have an important impact on the development of infectious diseases, but little is known about their potential predictive value in critically ill patients. Here, we used unsupervised flow cytometry analyses to quantify MDSC-like cells in healthy subjects challenged with endotoxin and in critically ill patients admitted to intensive care units and at risk of developing infections. Cells phenotypically similar to PMN-MDSCs and M-MDSCs increased after endotoxin challenge. Similar cells were elevated in patients at ICU admission and normalized at ICU discharge. A subpopulation of M-MDSC-like cells expressing intermediate levels of CD15 (CD15^int M-MDSCs) was associated with overall mortality (p = 0.02). Interestingly, the high abundance of PMN-MDSCs and CD15^int M-MDSCs was a good predictor of mortality (p = 0.0046 and 0.014), with area under the ROC curve for mortality of 0.70 (95% CI = 0.4–1.0) and 0.86 (0.62–1.0), respectively. Overall, our observations support the idea that MDSCs represent biomarkers for sepsis and that flow cytometry monitoring of MDSCs may be used to risk-stratify ICU patients for targeted therapy.