Adaptation of HIV-1 Envelope Glycoprotein gp120 to Humoral Immunity over the Course of the Epidemic

Since 2009, a large panel of broad and potent monoclonal neutralizing antibodies (MoNAbs) against HIV-1 have been isolated. These MoNAbs can protect from lllV-1 infection and suppress established infection in animal models. Because their efficacy should be evaluated in human clinical trials, it is of importance to define the sensitivity of the most contemporary transmitted variants to these MoNAbs. We, and others previously, reported that HIV-1 has become more resistant to neutralization over the course of the epidemic (Bunnik et al., Nature Med 2010, Bouvin-Pley et al., PloS Pathog 2013). Methods: Here we extended the analyses to the most potent MoNAbs described since then, either more recently isolated or improved by structure-based gene modifications. Results: We fully confirmed the first observations showing an increasing resistance of HIV-1 clade B over time to MoNAbs targeting the major gp l20 epitopes but not to MoNAbs targeting the gp41 MPER. Despite this evolution, some MoNAbs still were able to neutralize efficiently the most recently transmitted HIV-1 variants (2006-2010). The most potent MoNAbs were the bi-specific PG9- and PG16-iMab that alone were able to neutralize an variants at less than 0.4 mg/mL. The sensitivity to iMAb remained similar over time, suggesting that the trend of increasing resistance to PG9-/PG16-iMAb may be attributed only to die antigen binding domain of PG9/PG16. NIH45-46m2 (and -m7), 10-1074 and 10E8 were also highly potent and, if combined, reached the potency of PG9-/PG16-iMAb. We also observed that 3BNC 117 was almost as potent as the modified NIH45-46 antibodies, and that the lama-derived JM4IgG2b was the most potent Ab among those that do not target the major gp 120 neutralizing epitopes. Conclusions: These data clearly suggest a continuous drift of the env gene of HIV-1 elude B over the epidemic, and that not a single epitope is concerned but the entire gp120 as a whole. The consequences of this adaptation on the envelope functionality are being explored

Research for an immunization strategy capable to induce a broadly neutralizing antibodies response against HIV-1

La difficulté à induire des anticorps capables de neutraliser (anticorps neutralisants, AcN) la très grande diversité des isolats circulants du VIH-1 reste à l’heure actuelle un obstacle majeur au développement d'un vaccin préventif contre le VIH-1. L’objectif du projet a été de déterminer quels étaient les épitopes neutralisants les plus conservés au sein des 4 groupes M, N, O et P de VIH-1 puis de concevoir un immunogène qui serait capable d’induire la production d’AcN anti-VIH-1. Nous avons montré que l’épitope N160-glycane dépendant de la région V1/V2 de l’enveloppe virale est le plus conservé au sein des 4 groupes du VIH-1 (Morgand et al., JAIDS 2016). Nous avons ensuite montré la faisabilité d’obtenir, en système d’expression transitoire, des particules chimères constituées de la protéine d’enveloppe HBs du virus de l’hépatite B exprimant à leur surface les glycoprotéines d’enveloppe de différents groupes et sous-type du VIH-1. Malgré la présence de certains épitopes neutralisants (supersite N332-V3, site de liaison au CD4, région MPER- membrane proximal external region-), les épitopes d’intérêt de la région V1/V2 ne sont pas exposés sur ces particules chimères.The difficulty to induce antibodies able to neutralize (neutralizing antibodies, NAb) the large diversity of HIV- 1 isolates remains a major hurdle toward the development of an anti-HIV-1 vaccine. The aim of our study was first, to identify which epitopes are the most conserved within the 4 HIV-1 groups (M, N, O, P) and then, to design an immunogen that would be able to induce NAb against HIV-1. We showed that the V1/V2 N160- glycan epitope is the most conserved within the 4 HIV-1 groups (Morgand et al., JAIDS 2016). Subsequently, we showed the feasibility to generate chimeric particles based on the HBs envelope protein exposing the envelope glycoproteins of different groups and subtypes of HIV-1 at their surface. Although we demonstrated the presence of several neutralizing epitopes on these chimeric particles (N332-V3 supersite, CD4 binding site, membrane proximal external region), none of them exposed the V1/V2 epitopes of interest

Etude comparative de l'immunogénicité des virus de l'immunodéficience humaine de type 1 circulant à différentes périodes de l'épidémie

TOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF

Construction and Validation of an Individual Deprivation Index: a Study Based on a Representative Cohort of the Paris Metropolitan Area

International audienceThe association between health status and deprivation is well established. However, it is difficult to measure deprivation at an individual level and already-existing indices in France are not validated or do not meet the needs of health practitioners. The aim of this work was to establish a validated, easy-to-use, multidimensional, relevant index that was representative of the population in the Paris metropolitan area. From the SIRS 2010 cohort study, 14 socio-economic characteristics were selected: health insurance, educational background, socio-professional category, professional status, feelings of loneliness, emotional situation, household type, income, perceived financial situation, social support (support in daily life, financial and emotional), housing situation, and migration origin. In addition, a total of 12 health status, healthcare use, and nutrition-related variables were also selected. Content validity and internal validity of the index were explored. The 14 socio-economic indicators were associated to varying degrees with poorer health status, less use of healthcare, and poorer nutrition and were distributed across the 14 multiple-choice questions of the index. Each answer was rated from 0 to 2. The index value of 10 that isolates 20% of the most deprived individuals was used as threshold. “Being deprived,” as defined with this value, was significantly associated with 9 of the 12 studied health variables. This index could be a relevant instrument in the assessment of deprivation and social inequalities of health

Endocrine Disruptors and Pregnancy: Knowledge, Attitudes and Prevention Behaviors of French Women

Endocrine disrupting chemicals (EDC) are environmental exposure factors that are rarely reported in clinical practice, particularly during pregnancy. This study aimed to describe women’s knowledge, attitudes and behaviors towards EDC exposure. A study was conducted in the French Department of Vienne between 2014 and 2016 and comprised semi-structured interviews with pregnant women, a focus group of professionals in perinatology and environmental health, and the administration of a psychosocial questionnaire comprising scores in 300 pregnant or in postpartum period women. The mean score of knowledge was 42.9 ± 9.8 out of 100 (from 13.5 to 75.7). Exposure attitude was determined by risk perception. Mean level of cues to action to reduce their EDC exposure was estimated at 56.9 ± 22.5 out of 100 (from 0 to 100). Anxiety was significantly increased after the questionnaire. Anxiety about EDC was associated with a high score of knowledge (OR = 2.30, 95% CI (1.12–4.71)) and with no pregnancy anxiety (OR = 0.57, 95% CI (0.34–0.95)). Our findings suggest that healthcare providers should consider pregnant women’s knowledge and perceptions, possibilities of action, and be careful not to increase their anxiety when advising them about EDC and environmental exposure

Optimized fractionated radiotherapy with anti-PD-L1 and anti-TIGIT: a promising new combination

International audienc

Evidence for a Continuous Drift of the HIV-1 Species towards Higher Resistance to Neutralizing Antibodies over the Course of the Epidemic

<div><p>We compared the neutralization sensitivity of early/transmitted HIV-1 variants from patients infected by subtype B viruses at 3 periods of the epidemic (1987–1991, 1996–2000, 2006–2010). Infectious pseudotyped viruses expressing envelope glycoproteins representative of the viral quasi-species infecting each patient were tested for sensitivity to neutralization by pools of sera from HIV-1 chronically infected patients and by an updated panel of 13 human monoclonal neutralizing antibodies (HuMoNAbs). A progressive significantly enhanced resistance to neutralization was observed over calendar time, by both human sera and most of the HuMoNAbs tested (b12, VRC01, VRC03, NIH45-46^G54W, PG9, PG16, PGT121, PGT128, PGT145). Despite this evolution, a combination of two HuMoNAbs (NIH45-46^G54W and PGT128) still would efficiently neutralize the most contemporary transmitted variants. In addition, we observed a significant reduction of the heterologous neutralizing activity of sera from individuals infected most recently (2003–2007) compared to patients infected earlier (1987–1991), suggesting that the increasing resistance of the HIV species to neutralization over time coincided with a decreased immunogenicity. These data provide evidence for an ongoing adaptation of the HIV-1 species to the humoral immunity of the human population, which may add an additional obstacle to the design of an efficient HIV-1 vaccine.</p></div

Phylogenetic analysis of full-length<i>env</i> sequences.

<p>The 40 <i>env</i> sequences of the early/transmitted viruses included in our study were aligned with 160 <i>env</i> sequences isolated at time of primo-infection from clade B -infected patients, with documented year (1990–2009) and country (25 were from Europe, 113 from USA, 6 from Australia, 15 from Trinidad and 1 from Zambia) of infection. A neighbor-joining tree was constructed using the MEGA software <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003477#ppat.1003477-Tamura2" target="_blank">[89]</a>. Open, grey filled and black filled circles identify the sequences derived from the historical, intermediate and contemporary patients of our study, respectively. Bootstrap values above 70% are indicated.</p

Enhanced resistance of clade B early/transmitted HIV-1 variants to neutralization by HuMoNAbs over the course of the epidemic.

<p>[A to E] Comparison of the neutralization sensitivity of Env-pseudotyped viruses derived from historical patients (HP, n = 11), intermediate patients (IP, n = 15) and contemporary patients (CP, n = 14) by b12, VRC01, VRC03 and NIH45-46G54W [A], PG9, PG16 and PGT145 [B], PGT121, PGT128, PGT135 and 2G12 [C] and 2F5 and 4E10 [D]. Box plots show the distribution of antibody titers (IC₅₀) of each HuMoNAb towards pseudotyped viruses of each period; the horizontal lines represent the 10^th, median and 90^th percentiles. Each data represents the mean value of the assay performed in duplicate. Differences of neutralization sensitivity between viruses over calendar time were evaluated using a Jonckheere-Terpstra test. [E] Comparison of the neutralization coverage of each HuMoNabs used at various concentrations (IC₅₀≤10 µg/mL, ≤1 µg/mL or ≤0.01 µg/mL) towards pseudotyped viruses from HP, IP and CP. Differences of neutralization coverage of viruses from HP to CP were evaluated using a Chi² test for trend.</p