Relationship between latent and rebound viruses in a clinical trial of anti-HIV-1 antibody 3BNC117.

A clinical trial was performed to evaluate 3BNC117, a potent anti-HIV-1 antibody, in infected individuals during suppressive antiretroviral therapy and subsequent analytical treatment interruption (ATI). The circulating reservoir was evaluated by quantitative and qualitative viral outgrowth assay (Q2VOA) at entry and after 6 mo. There were no significant quantitative changes in the size of the reservoir before ATI, and the composition of circulating reservoir clones varied in a manner that did not correlate with 3BNC117 sensitivity. 3BNC117 binding site amino acid variants found in rebound viruses preexisted in the latent reservoir. However, only 3 of 217 rebound viruses were identical to 868 latent viruses isolated by Q2VOA and near full-length sequencing. Instead, 63% of the rebound viruses appeared to be recombinants, even in individuals with 3BNC117-resistant reservoir viruses. In conclusion, viruses emerging during ATI in individuals treated with 3BNC117 are not the dominant species found in the circulating latent reservoir, but frequently appear to represent recombinants of latent viruses

Population Genetics of Franciscana Dolphins (Pontoporia blainvillei): Introducing a New Population from the Southern Edge of Their Distribution

Due to anthropogenic factors, the franciscana dolphin, Pontoporia blainvillei, is the most threatened small cetacean on the Atlantic coast of South America. Four Franciscana Management Areas have been proposed: Espiritu Santo to Rio de Janeiro (FMA I), São Paulo to Santa Catarina (FMA II), Rio Grande do Sul to Uruguay (FMA III), and Argentina (FMA IV). Further genetic studies distinguished additional populations within these FMAs. We analyzed the population structure, phylogeography, and demographic history in the southernmost portion of the species range. From the analysis of mitochondrial DNA control region sequences, 5 novel haplotypes were found, totalizing 60 haplotypes for the entire distribution range. The haplotype network did not show an apparent phylogeographical signal for the southern FMAs. Two populations were identified: Monte Hermoso (MH) and Necochea (NC)+Claromecó (CL)+Río Negro (RN). The low levels of genetic variability, the relative constant size over time, and the low levels of gene flow may indicate that MH has been colonized by a few maternal lineages and became isolated from geographically close populations. The apparent increase in NC+CL+RN size would be consistent with the higher genetic variability found, since genetic diversity is generally higher in older and expanding populations. Additionally, RN may have experienced a recent split from CL and NC; current high levels of gene flow may be occurring between the latter ones. FMA IV would comprise four franciscana dolphin populations: Samborombón West+Samborombón South, Cabo San Antonio+Buenos Aires East, NC+CL+Buenos Aires Southwest+RN and MH. Results achieved in this study need to be taken into account in order to ensure the long-term survival of the species.Fil: Gariboldi, María Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Tunez, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Luján; ArgentinaFil: Dejean, Cristina Beatriz. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Ciencias Antropológicas. Sección Antropología Biológica; ArgentinaFil: Failla, Mauricio. Fundación Cethus; ArgentinaFil: Vitullo, Alfredo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Negri, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales ; ArgentinaFil: Cappozzo, Humberto Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales ; Argentin

Angiotensin-converting enzyme I/D polymorphism and preeclampsia risk: evidence of small-study bias

BACKGROUND: Inappropriate activation of the renin-angiotensin system may play a part in the development of preeclampsia. An insertion/deletion polymorphism within the angiotensin-I converting enzyme gene (ACE-I/D) has shown to be reliably associated with differences in angiotensin-converting enzyme (ACE) activity. However, previous studies of the ACE-I/D variant and preeclampsia have been individually underpowered to detect plausible genotypic risks. METHODS AND FINDINGS: A prospective case-control study was conducted in 1,711 unrelated young pregnant women (665 preeclamptic and 1,046 healthy pregnant controls) recruited from five Colombian cities. Maternal blood was obtained to genotype for the ACE-I/D polymorphism. Crude and adjusted odds ratio (OR) and 95% confidence interval (CI) using logistic regression models were obtained to evaluate the strength of the association between ACE-I/D variant and preeclampsia risk. A meta-analysis was then undertaken of all published studies to February 2006 evaluating the ACE-I/D variant in preeclampsia. An additive model (per-D-allele) revealed a null association between the ACE-I/D variant and preeclampsia risk (crude OR = 0.95 [95% CI, 0.81-1.10]) in the new case-control study. Similar results were obtained after adjusting for confounders (adjusted per-allele OR = 0.90 [95% CI, 0.77-1.06]) and using other genetic models of inheritance. A meta-analysis (2,596 cases and 3,828 controls from 22 studies) showed a per-allele OR of 1.26 (95% CI, 1.07-1.49). An analysis stratified by study size showed an attenuated OR toward the null as study size increased. CONCLUSIONS: It is highly likely that the observed small nominal increase in risk of preeclampsia associated with the ACE D-allele is due to small-study bias, similar to that observed in cardiovascular disease. Reliable assessment of the origins of preeclampsia using a genetic approach may require the establishment of a collaborating consortium to generate a dataset of adequate size

Convergent Antibody Responses to SARS-CoV-2 Infection in Convalescent Individuals

During the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-2. Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal pseudovirus neutralizing titres: less than 1:50 in 33% and below 1:1,000 in 79%, while only 1% showed titres above 1:5,000. Antibody sequencing revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titres, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC₅₀ values) as low as single digit nanograms per millitre. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective

Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals

Monotherapy of HIV-1 infection with single antiretroviral agents is ineffective because error-prone HIV-1 replication leads to the production of drug-resistant viral variants(1,2). Combinations of drugs can establish long-term control, however, antiretroviral therapy (ART) requires daily dosing, can cause side effects and does not eradicate the infection(3,4). Although anti-HIV-1 antibodies constitute a potential alternative to ART(5,6), treatment of viremic individuals with a single antibody also results in emergence of resistant viral variants(7-9). Moreover, combinations of first-generation anti-HIV-1 broadly neutralizing antibodies (bNAbs) had little measurable effect on the infection(10-12). Here we report on a phase 1b clinical trial (NCT02825797) in which two potent bNAbs, 3BNC117(13) and 10-1074(14), were administered in combination to seven HIV-1 viremic individuals. Infusions of 30 mg kg(-1) of each of the antibodies were well-tolerated. In the four individuals with dual antibody-sensitive viruses, immunotherapy resulted in an average reduction in HIV-1 viral load of 2.05 log(10) copies per ml that remained significantly reduced for three months following the first of up to three infusions. In addition, none of these individuals developed resistance to both antibodies. Larger studies will be necessary to confirm the efficacy of antibody combinations in reducing HIV-1 viremia and limiting the emergence of resistant viral variants