The breadth of maternal HIV-1 specific neutralizing antibodies is not associated with a lower risk of mother-to-infant transmission

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Human immunodeficiency virus type-1 (HIV-1) continues to evolve in presence of broadly neutralizing antibodies more than ten years after infection.

BACKGROUND: The evolution of HIV-1 and its immune escape to autologous neutralizing antibodies (Nabs) during the acute/early phases of infection have been analyzed in depth in many studies. In contrast, little is known about neither the long-term evolution of the virus in patients who developed broadly Nabs (bNabs) or the mechanism of escape in presence of these bNabs. RESULTS: We have studied the viral population infecting a long term non progressor HIV-1 infected patient who had developed broadly neutralizing antibodies toward all tier 2/3 viruses (6 clades) tested, 9 years after infection, and was then followed up over 7 years. The autologous neutralization titers of the sequential sera toward env variants representative of the viral population significantly increased during the follow-up period. The most resistant pseudotyped virus was identified at the last visit suggesting that it represented a late emerging escape variant. We identified 5 amino acids substitutions that appeared associated with escape to broadly neutralizing antibodies. They were V319I/S, R/K355T, R/W429G, Q460E and G/T463E, in V3, C3 and V5 regions. CONCLUSION: This study showed that HIV-1 may continue to evolve in presence of both broadly neutralizing antibodies and increasing autologous neutralizing activity more than 10 years post-infection

Continuous evolution of HIV-1 more than ten years after infection in an elite neutralizer

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Estimating the Timing of Mother-to-Child Transmission of the Human Immunodeficiency Virus Type 1 Using a Viral Molecular Evolution Model

Background: Mother-to-child transmission (MTCT) is responsible for most pediatric HIV-1 infections worldwide. It can occur during pregnancy, labor, or breastfeeding. Numerous studies have used coalescent and molecular clock methods to understand the epidemic history of HIV-1, but the timing of vertical transmission has not been studied using these methods. Taking advantage of the constant accumulation of HIV genetic variation over time and using longitudinally sampled viral sequences, we used a coalescent approach to investigate the timing of MTCT. Materials and Methods Six-hundred and twenty-two clonal env sequences from the RNA and DNA viral population were longitudinally sampled from nine HIV-1 infected mother-and-child pairs [range: 277–1034 days]. For each transmission pair, timing of MTCT was determined using a coalescent-based model within a Bayesian statistical framework. Results were compared with available estimates of MTCT timing obtained with the classic biomedical approach based on serial HIV DNA detection by PCR assays. Results: Four children were infected during pregnancy, whereas the remaining five children were infected at time of delivery. For eight out of nine pairs, results were consistent with the transmission periods assessed by standard PCR-based assay. The discordance in the remaining case was likely confused by co-infection, with simultaneous introduction of multiple maternal viral variants at the time of delivery. Conclusions: The study provided the opportunity to validate the Bayesian coalescent approach that determines the timing of MTCT of HIV-1. It illustrates the power of population genetics approaches to reliably estimate the timing of transmission events and deepens our knowledge about the dynamics of viral evolution in HIV-infected children, accounting for the complexity of multiple transmission events

P04-17. The N-glycosylation sites N295, N332 and N392 of gp120 are necessary but not sufficient for HIV-1 to be neutralized by 2G12

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Cost-effectiveness of Universal Hepatitis C Virus Screening of Pregnant Women in the United States

BACKGROUND:Hepatitis C virus' (HCV) chronic prevalence among pregnant women in the United States doubled nationally from 2009-2014 (~0.7%), yet many cases remain undiagnosed. Screening pregnant women is not recommended by the Society of Maternal-Fetal Medicine or the Centers for Disease Control and Prevention, despite new American Association For the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA) guidelines recommending screening for this group. We assessed the cost-effectiveness of HCV screening for pregnant women in the United States. METHODS:An HCV natural history Markov model was used to evaluate the cost-effectiveness of universal HCV screening of pregnant women, followed by treatment after pregnancy, compared to background risk-based screening from a health-care payer perspective. We assumed a HCV chronic prevalence of 0.73% among pregnant women, based on national data. We assumed no Medicaid reimbursement restrictions by fibrosis stage at baseline, but explored differing restrictions in sensitivity analyses. We assessed costs (in US dollars) and health outcomes (in quality-adjusted life-years [QALYs]) over a lifetime horizon, using new HCV drug costs of $25 000/treatment. We assessed mean incremental cost-effectiveness ratios (ICERs) under a willingness-to-pay threshold of$50 000/QALY gained. We additionally evaluated the potential population impact. RESULTS:Universal antenatal screening was cost-effective in all treatment eligibility scenarios (mean ICER <$3000/QALY gained). Screening remained cost-effective at a prevalence of 0.07%, which is the lowest estimated prevalence in the United States (in Hawaii). Screening the ~5.04 million pregnant women in 2018 could result in the detection and treatment of 33 000 women, based on current fibrosis restrictions. CONCLUSIONS:Universal screening for HCV among pregnant women in the United States is cost-effective and should be recommended nationally

The role of neutralizing antibodies in prevention of HIV-1 infection: what can we learn from the mother-to-child transmission context?

International audienceIn most viral infections, protection through existing vaccines is linked to the presence of vaccine-induced neutralizing antibodies (NAbs). However, more than 30 years after the identification of AIDS, the design of an immunogen able to induce antibodies that would neutralize the highly diverse HIV-1 variants remains one of the most puzzling challenges of the human microbiology. The role of antibodies in protection against HIV-1 can be studied in a natural situation that is the mother-to-child transmission (MTCT) context. Indeed, at least at the end of pregnancy, maternal antibodies of the IgG class are passively transferred to the fetus protecting the neonate from new infections during the first weeks or months of life. During the last few years, strong data, presented in this review, have suggested that some NAbs might confer protection toward neonatal HIV-1 infection. In cases of transmission, it has been shown that the viral population that is transmitted from the mother to the infant is usually homogeneous, genetically restricted and resistant to the maternal HIV-1-specific antibodies. Although the breath of neutralization was not associated with protection, it has not been excluded that NAbs toward specific HIV-1 strains might be associated with a lower rate of MTCT. A better identification of the antibody specificities that could mediate protection toward MTCT of HIV-1 would provide important insights into the antibody responses that would be useful for vaccine development. The most convincing data suggesting that NAbs migh confer protection against HIV-1 infection have been obtained by experiments of passive immunization of newborn macaques with the first generation of human monoclonal broadly neutralizing antibodies (HuMoNAbs). However, these studies, which included only a few selected subtype B challenge viruses, provide data limited to protection against a very restricted number of isolates and therefore have limitations in addressing the hypervariability of HIV-1. The recent identification of highly potent second-generation cross-clade HuMoNAbs provides a new opportunity to evaluate the efficacy of passive immunization to prevent MTCT of HIV-1

Learning From Full Characterization of HIV Proviruses in People Receiving Long-Acting Cabotegravir/Rilpivirine With a History of Replication on the Antiretroviral Classes.

BACKGROUND: To better understand factors associated with virologic response, we retrospectively characterized the HIV proviruses of 7 people with HIV who received long-acting cabotegravir/rilpivirine (CAB/RPV-LA) and were selected according to the following criteria: virologic control achieved despite a history of viral replication on 1 or both corresponding antiretroviral classes (n = 6) and virologic failure (VF) after CAB/RPV-LA initiation (n = 1). METHODS: Last available blood samples before the initiation of CAB/RPV-LA were analyzed retrospectively. Near full-length HIV DNA genome haplotypes were inferred from Nanopore sequencing by the in vivo Genome Diversity Analyzer to search for archived drug resistance mutations (DRMs) and evaluate the frequency and intactness of proviruses harboring DRMs. RESULTS: Archived DRMs including G-to-A mutations were found in samples from 3 patients who maintained virologic control. Genomes harboring DRMs were majorly in minority variants (<20%) and were defective in all cases except for 1 participant. In this participant, intact genomes with the H221Y mutation on reverse transcriptase were detected representing 11 copies per 106 peripheral blood mononuclear cells. The other mutations observed in the participants of the study resulted most likely from hypermutations. The patient with VF presented archived mutations, all associated with defects. Other factors could explain this VF. CONCLUSIONS: Our findings highlight the difficulty in interpreting the clinical significance of DRMs when detected in proviral DNA and the need to filter out hypermutated sequences. Detected DRMs could be harbored by defective archived genomes unlikely to contribute to treatment failure

Modeling the population-level impact of opioid agonist treatment on mortality among people accessing treatment between 2001 and 2020 in New South Wales, Australia

Background and AimsThe individual-level effectiveness of opioid agonist treatment (OAT) in reducing mortality is well established, but there is less evidence on population-level benefits. We use modeling informed with linked data from the OAT program in New South Wales (NSW), Australia, to estimate the impact of OAT provision in the community and prisons on mortality and the impact of eliminating excess mortality during OAT initiation/discontinuation.DesignDynamic modeling.Setting and participantsA cohort of 49 359 individuals who ever received OAT in NSW from 2001 to 2018.MeasurementsReceipt of OAT was represented through five stages: (i) first month on OAT, (ii) short (1–9 months) and (iii) longer (9+ months) duration on OAT, (iv) first month following OAT discontinuation and (v) rest of time following OAT discontinuation. Incarceration was represented as four strata: (i) never or not incarcerated in the past year, (ii) currently incarcerated, (iii) released from prison within the past month and (iv) released from prison 1–12 months ago. The model incorporated elevated mortality post-release from prison and OAT impact on reducing mortality and incarceration.FindingsAmong the cohort, mortality was 0.9 per 100 person-years, OAT coverage and retention remained high (> 50%, 1.74 years/episode). During 2001–20, we estimate that OAT provision reduced overdose and other cause mortality among the cohort by 52.8% [95% credible interval (CrI) = 49.4–56.9%] and 26.6% (95% CrI =22.1–30.5%), respectively. We estimate 1.2 deaths averted and 9.7 life-years gained per 100 person-years on OAT. Prison OAT with post-release OAT-linkage accounted for 12.4% (95% CrI = 11.5–13.5%) of all deaths averted by the OAT program, primarily through preventing deaths in the first month post-release. Preventing elevated mortality during OAT initiation and discontinuation could have averted up to 1.4% (95% CrI =  0.8–2.0%) and 3.0% (95% CrI = 2.1–5.3%) of deaths, respectively.ConclusionThe community and prison opioid agonist treatment program in New South Wales, Australia appears to have substantially reduced population-level overdose and all-cause mortality in the past 20 years, partially due to high retention

Characterizing genetic transmission networks among newly diagnosed HIV-1 infected individuals in eastern China: 2012–2016

We aimed to elucidate the characteristics of HIV molecular epidemiology and identify transmission hubs in eastern China using genetic transmission network and lineage analyses. HIV-TRACE was used to infer putative relationships. Across the range of epidemiologically-plausible genetic distance (GD) thresholds (0.1-2.0%), a sensitivity analysis was performed to determine the optimal threshold, generating the maximum number of transmission clusters and providing reliable resolution without merging different small clusters into a single large cluster. Characteristics of genetically linked individuals were analyzed using logistic regression. Assortativity (shared characteristics) analysis was performed to infer shared attributes between putative partners. 1,993 persons living with HIV-1 were enrolled. The determined GD thresholds within subtypes CRF07_BC, CRF01_AE, and B were 0.5%, 1.2%, and 1.7%, respectively, and 826 of 1,993 (41.4%) sequences were linked with at least one other sequence, forming 188 transmission clusters of 2-80 sequences. Clustering rates for the main subtypes CRF01_AE, CRF07_BC, and B were 50.9% (523/1027), 34.2% (256/749), and 32.1% (25/78), respectively. Median cluster sizes of these subtypes were 2 (2-52, n = 523), 2 (2-80, n = 256), and 3 (2-6, n = 25), respectively. Subtypes in individuals diagnosed and residing in Hangzhou city (OR = 1.423, 95% CI: 1.168-1.734) and men who have sex with men (MSM) were more likely to cluster. Assortativity analysis revealed individuals were more likely to be genetically linked to individuals from the same age group (AIage = 0.090, P<0.001) and the same area of residency in Zhejiang (AIcity = 0.078, P<0.001). Additionally, students living with HIV were more likely to be linked with students than show a random distribution (AI student = 0.740, P<0.01). These results highlight the importance of Hangzhou City in the regional epidemic and show that MSM comprise the population rapidly transmitting HIV in Zhejiang Province. We also provide a molecular epidemiology framework for improving our understanding of HIV transmission dynamics in eastern China