Escape of HIV-1 from a Small Molecule CCR5 Inhibitor Is Not Associated with a Fitness Loss

Fitness is a parameter used to quantify how well an organism adapts to its environment; in the present study, fitness is a measure of how well strains of human immunodeficiency virus type 1 (HIV-1) replicate in tissue culture. When HIV-1 develops resistance in vitro or in vivo to antiretroviral drugs such as reverse transcriptase or protease inhibitors, its fitness is often impaired. Here, we have investigated whether the development of resistance in vitro to a small molecule CCR5 inhibitor, AD101, has an associated fitness cost. To do this, we developed a growth-competition assay involving dual infections with molecularly cloned viruses that are essentially isogenic outside the env genes under study. Real-time TaqMan quantitative PCR (QPCR) was used to quantify each competing virus individually via probes specific to different, phenotypically silent target sequences engineered within their vif genes. Head-to-head competition assays of env clones derived from the AD101 escape mutant isolate, the inhibitor-sensitive parental virus, and a passage control virus showed that AD101 resistance was not associated with a fitness loss. This observation is consistent with the retention of the resistant phenotype when the escape mutant was cultured for a total of 20 passages in the absence of the selecting compound. Amino acid substitutions in the V3 region of gp120 that confer complete AD101 resistance cause a fitness loss when introduced into an AD101-sensitive, parental clone; however, in the resistant isolate, changes elsewhere in env that occurred prior to the substitutions within V3 appear to compensate for the adverse effect of the V3 changes on replicative capacity. These in vitro studies may have implications for the development and management of resistance to other CCR5 inhibitors that are being evaluated clinically for the treatment of HIV-1 infection

Совершенствование организационной культуры в образовательной организации на примере МАОУ СОШ № 3

Проблема исследования заключается в необходимости совершенствования организационной культуры МАОУ СОШ № 3.Целью выпускной квалификационной работы является анализ организационной культуры МАОУ СОШ № 3 и ее совершенствование. Объект исследования: организационная культура образовательного учреждения. Предмет исследования: совершенствование организационной культуры образовательной организации МАОУ СОШ № 3.Структура работы. Работа состоит из введения, двух глав, списка использованных источников

Global genetic variation of HIV-1 infection

Variability, both at the population (interhost) as well as at the individual (intrahost) level is a key property of HIV that stems mainly from the inherent infidelity of the reverse transcriptase enzyme that the virus uses to transcribe its RNA genome into DNA so that it may be integrated into the human genetic material and propagated along with it. The lack of proofreading mechanisms, high turnover of virions, and propensity for recombination also contribute to the extensive variability of HIV. These parameters provide the virus quasispecies with an impressive capacity to adapt to immunologic, pharmacologic or other selection pressures and have important implications for the diagnosis of new infections, the monitoring of antiretroviral treatment response, and effective vaccine(s) design. Herein, we discuss in detail the global genetic variation of HIV-1 infection

Human genetic factors associated with susceptibility to SARS-CoV-2 infection and COVID-19 disease severity

BACKGROUND: The emergence of the novel coronavirus in Wuhan, Hubei Province, China, in December 2019 marked the synchronization of the world to a peculiar clock that is counting infected cases and deaths instead of hours and minutes. The pandemic, highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has indeed caused considerable morbidity and mortality and drastically changed our everyday lives. As we continue to become acquainted with the seventh coronavirus known to infect our species, a number of its characteristics keep surprising us. Among those is the wide spectrum of clinical manifestations of the resulting coronavirus disease 2019 (COVID-19), which ranges from asymptomatic or mildly symptomatic infections to severe pneumonia, respiratory failure, and death. MAIN BODY: Data, now from patient populations, are beginning to accumulate on human genetic factors that may contribute to the observed diversified disease severity. Therefore, we deemed it prudent to review the associations between specific human genetic variants and clinical disease severity or susceptibility to infection that have been reported in the literature to date (at the time of writing this article in early August 2020 with updates in mid-September). With this work, we hope (i) to assist the fast-paced biomedical research efforts to combat the virus by critically summarizing current knowledge on the potential role of host genetics, and (ii) to help guide current genetics and genomics research towards candidate gene variants that warrant further investigation in larger studies. We found that determinants of differing severity of COVID-19 predominantly include components of the immune response to the virus, while determinants of differing susceptibility to SARS-CoV-2 mostly entail genes related to the initial stages of infection (i.e., binding of the cell surface receptor and entry). CNCLUSION: Elucidating the genetic determinants of COVID-19 severity and susceptibility to SARS-CoV-2 infection would allow for the stratification of individuals according to risk so that those at high risk would be prioritized for immunization, for example, if or when safe and effective vaccines are developed. Our enhanced understanding of the underlying biological mechanisms could also guide personalized therapeutics. Such knowledge is already beginning to provide clues that help explain, at least in part, current epidemiologic observations regarding the typically more severe or benign disease course in older males and children, respectively

Data-based analysis, modelling and forecasting of the COVID-19 outbreak

Since the first suspected case of coronavirus disease-2019 (COVID-19) on December 1st, 2019, in Wuhan, Hubei Province, China, a total of 40,235 confirmed cases and 909 deaths have been reported in China up to February 10, 2020, evoking fear locally and internationally. Here, based on the publicly available epidemiological data for Hubei, China from January 11 to February 10, 2020, we provide estimates of the main epidemiological parameters. In particular, we provide an estimation of the case fatality and case recovery ratios, along with their 90% confidence intervals as the outbreak evolves. On the basis of a Susceptible-Infectious-Recovered-Dead (SIDR) model, we provide estimations of the basic reproduction number (R0), and the per day infection mortality and recovery rates. By calibrating the parameters of the SIRD model to the reported data, we also attempt to forecast the evolution of the outbreak at the epicenter three weeks ahead, i.e. until February 29. As the number of infected individuals, especially of those with asymptomatic or mild courses, is suspected to be much higher than the official numbers, which can be considered only as a subset of the actual numbers of infected and recovered cases in the total population, we have repeated the calculations under a second scenario that considers twenty times the number of confirmed infected cases and forty times the number of recovered, leaving the number of deaths unchanged. Based on the reported data, the expected value of R0 as computed considering the period from the 11th of January until the 18th of January, using the official counts of confirmed cases was found to be ∼4.6, while the one computed under the second scenario was found to be ∼3.2. Thus, based on the SIRD simulations, the estimated average value of R0 was found to be ∼2.6 based on confirmed cases and ∼2 based on the second scenario. Our forecasting flashes a note of caution for the presently unfolding outbreak in China. Based on the official counts for confirmed cases, the simulations suggest that the cumulative number of infected could reach 180,000 (with a lower bound of 45,000) by February 29. Regarding the number of deaths, simulations forecast that on the basis of the up to the 10th of February reported data, the death toll might exceed 2,700 (as a lower bound) by February 29. Our analysis further reveals a significant decline of the case fatality ratio from January 26 to which various factors may have contributed, such as the severe control measures taken in Hubei, China (e.g. quarantine and hospitalization of infected individuals), but mainly because of the fact that the actual cumulative numbers of infected and recovered cases in the population most likely are much higher than the reported ones. Thus, in a scenario where we have taken twenty times the confirmed number of infected and forty times the confirmed number of recovered cases, the case fatality ratio is around ∼0.15% in the total population. Importantly, based on this scenario, simulations suggest a slow down of the outbreak in Hubei at the end of February

The Role of Oral Antivirals for COVID-19 Treatment in Shaping the Pandemic Landscape

Several vaccines against coronavirus disease 2019 (COVID-19) were developed and made available in a record time, just over a year after the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [...

SARS-CoV-2 Reinfections and Long COVID in the Post-Omicron Phase of the Pandemic

We are reviewing the current state of knowledge on the virological and immunological correlates of long COVID, focusing on recent evidence for the possible association between the increasing number of SARS-CoV-2 reinfections and the parallel pandemic of long COVID. The severity of reinfections largely depends on the severity of the initial episode; in turn, this is determined both by a combination of genetic factors, particularly related to the innate immune response, and by the pathogenicity of the specific variant, especially its ability to infect and induce syncytia formation at the lower respiratory tract. The cumulative risk of long COVID as well as of various cardiac, pulmonary, or neurological complications increases proportionally to the number of SARS-CoV-2 infections, primarily in the elderly. Therefore, the number of long COVID cases is expected to remain high in the future. Reinfections apparently increase the likelihood of long COVID, but less so if they are mild or asymptomatic as in children and adolescents. Strategies to prevent SARS-CoV-2 reinfections are urgently needed, primarily among older adults who have a higher burden of comorbidities. Follow-up studies using an established case definition and precise diagnostic criteria of long COVID in people with or without reinfection may further elucidate the contribution of SARS-CoV-2 reinfections to the long COVID burden. Although accumulating evidence supports vaccination, both before and after the SARS-CoV-2 infection, as a preventive strategy to reduce the risk of long COVID, more robust comparative observational studies, including randomized trials, are needed to provide conclusive evidence of the effectiveness of vaccination in preventing or mitigating long COVID in all age groups. Thankfully, answers not only on the prevention, but also on treatment options and rates of recovery from long COVID are gradually starting to emerge

Declining seroprevalence of hepatitis A in Vojvodina, Serbia.

To assess the current hepatitis A virus (HAV) endemicity in the Autonomous Province of Vojvodina, Serbia, we examined the seroprevalence and susceptibility profiles of the general population. A serum bank of 3466 residual samples, collected in 2015-16 as per the specifications of the European Sero-Epidemiology Network 2 project (ESEN2), was tested for anti-HAV antibodies with an enzyme immunoassay. Relationships between anti-HAV positivity and demographic features of respondents were examined by univariable and multivariable analyses. Present-day HAV seroprevalence was compared with that obtained in 1978-79. Surveillance data for hepatitis A recorded between 2008 and 2017 were also analyzed. Age was the only demographic variable found to be independently associated with a HAV seropositive status. Seropositivity (17% overall vs. 79% in 1978-79) increased with age to a maximum of 90% in the elderly ≥60 years. Only 5% of subjects <30 years were seropositive, unlike the 44% of seropositives ≥30 years. The estimated age at midpoint of population immunity (AMPI) increased markedly from 14 years in the late 70s to 55 years in 2015-16. Meanwhile, disease incidence decreased noticeably in recent years (from 11 in 2008 to 2 per 100,000 population in 2017). In the ongoing pre-vaccine era, natural infection provides immunity for merely a third (31%) and two thirds (57%) of people in their 40s and 50s, respectively. Hence, the majority of people ≤40 years (94%) and middle-aged adults 40-49 years (69%) are susceptible to HAV. Older susceptible individuals, particularly those ≥50 years (24%), are prone to severe symptoms. Taken together, these changes reflect the epidemiological transition of Vojvodina and Serbia from high to very low HAV endemicity, thereby supporting the current national policy of immunization of only high-risk groups