Current status of HIV/AIDS in the ART era Yoshimura, Kazuhisa
Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy,
01/2017, Volume:
23, Issue:
1
Journal Article
Peer reviewed
Abstract Human immunodeficiency virus (HIV) spread to humans from chimpanzees (HIV-1 groups M and N), gorillas (HIV-1 groups P and O), and sooty mangabeys (HIV-2). HIV is spread mainly through blood ...or body fluids. Subjects can become infected with HIV by sexual contact, needle sharing, blood transfusions, or maternal transmissions as a blood-borne virus or via breast-milk. The incubation period of HIV-1 from infection to the development of AIDS ranges from 8 to 11 years. In the past 3 decades, HIV has caused a great burden to global wealth and health. According to the WHO global health survey, 36.7 million people were infected with HIV, causing 1.1 million deaths in 2015. Since the discovery of HIV-1, many anti-retroviral drugs have been developed. Following the discovery and wide-spread use of anti-retroviral therapy (ART) the life expectancy of HIV infected individuals has substantially increased. By 2015, all major guidelines recommended treating all HIV-infected adults regardless of their CD4 count. Despite effective ART with virological suppression, HIV-associated neurocognitive disorders (HAND), cardiovascular diseases (CVD), metabolic syndrome (MS), bone abnormalities and non-HIV-associated malignancies remain a major complication associated with HIV infection. In this review article, I would like to describe recent ART status and problems in the ART-era.
After the global spread of the SARS-CoV-2 Omicron BA.2, some BA.2 subvariants, including BA.2.9.1, BA.2.11, BA.2.12.1, BA.4, and BA.5, emerged in multiple countries. Our statistical analysis showed ...that the effective reproduction numbers of these BA.2 subvariants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1/2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. We further provided the structure of the BA.4/5 spike receptor-binding domain that binds to human ACE2 and considered how the substitutions in the BA.4/5 spike play roles in ACE2 binding and immune evasion. Moreover, experiments using hamsters suggested that BA.4/5 is more pathogenic than BA.2. Our multiscale investigations suggest that the risk of BA.2 subvariants, particularly BA.4/5, to global health is greater than that of original BA.2.
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•BA.4/5 is resistant to immunity induced by BA.1 and BA.2 infections•Substitutions in the BA.4/5 spike contribute to immune escape and ACE2 binding strength•BA.4/5 is more fusogenic and more efficiently spread in human lung cells than BA.2•BA.4/5 spike-bearing virus is more pathogenic than BA.2 spike-bearing virus
The SARS-CoV-2 Omicron variants BA.4 and BA.5 are currently causing infections and COVID-19 morbidities worldwide. Compared with the earlier variant BA.2, BA.4/5 shows more efficient replication and is more fusogenic. Structural views as well as in vivo studies in hamsters explain the antibody evasion and increased pathogenicity of BA.4/5 over BA.2.
While mRNA vaccines against SARS-CoV-2 are exceedingly effective in preventing symptomatic infection, their immune response features remain to be clarified. In the present prospective study, 225 ...healthy individuals in Japan, who received two BNT162b2 doses, were enrolled. Correlates of BNT162b2-elicited SARS-CoV-2-neutralizing activity (50% neutralization titer: NT
; assessed using infectious virions) with various determinants were examined and the potency of sera against variants of concerns was determined. Significant rise in NT
s was seen in sera on day 28 post-1st dose. A moderate inverse correlation was seen between NT
s and ages, but no correlation seen between NT
s and adverse effects. NT
s and SARS-CoV-2-S1-binding-IgG levels on day 28 post-1st dose and pain scores following the 2nd dose were greater in women than in men. The average half-life of NT
s was ~ 68 days, and 23.6% (49 out of 208 individuals) failed to show detectable neutralizing activity on day 150. While sera from elite-responders (NT
s > 1,500: the top 4% among the participants) potently to moderately blocked all variants of concerns examined, some sera with low NT
s failed to block the B.1.351-beta strain. Since BNT162b2-elicited immunity against SARS-CoV-2 is short, an additional vaccine or other protective measures are needed.
The inspection gallery of a dam is leached by reservoir water that has infiltrated through the rock-fill dam body from the high-pressure water area upstream (leakage), and groundwater seeping through ...the foundation bed which has been injected with ordinary Portland cement (OPC) grout. Seepage waters with a pH greater than 12 are characterized by the major components of Ca(OH)2 and alkali hydroxides, lower Mg2+ concentration and higher K+/Na+ molar ratio than those for river and spring waters and groundwater near the dam site, and the extensive carbonate deposits precipitated from the waters. During a low discharge period, NaOH was the major component because Ca2+ was removed as carbonate deposits. Based on the stable isotope ratios of hydrogen and oxygen in the water, which reflect the altitude effect, it was inferred that the seepage waters are supplied from the shallow groundwater near the dam site and that the leakage is a mixture of the seepage water and reservoir water. Alkali hydroxides and Ca(OH)2 cement porewaters formed during the early stages of hydration of OPC are still present in the cement mass after 46 years, and that the OPC still remains partially unhydrated. These highly alkaline porewaters have seeped through gaps of the concrete joint surfaces to discharge into the inspection gallery. The Ca(OH)2 concentration in the seepage was below the portlandite saturation, therefore, the grout-derived solutes are considered to have been diluted as they diffused into the shallow groundwater before being discharged with the groundwater seeping into the gallery due to the hydraulic head difference and mixed with the groundwater. Ca(OH)2 in the seepage reacted with atmospheric CO2 in the inspection gallery, and the carbon stable isotope ratio of the carbonate deposits produced in this way was unusually low, about −25‰ VPDB, due to the large disequilibrium isotope fractionation during the direct reaction of CO2 with OH− in the solution. In addition to the change in its discharge, the hyperalkaline seepage and the resulting carbonate deposits with unusually low δ13C values can be measures of the durability of the grout-treated foundation rock of the rock-fill dam, because the decrease in pH in the future is related to the instability of the grout hydration products by carbonation.
•Seepage waters with a pH greater than 12 have been observed in an inspection gallery of an over 46 years old rock-fill dam.•Hyperalkaline seepage waters are characterized by their high calcium and alkali hydroxides contents and by calcite deposits.•Altitude effect of hydrogen and oxygen isotope ratios of water could allow estimating their source waters.•The unusually low δ13C carbonate deposits were produced by the direct reaction of atmospheric CO2 with OH- in the solution.•The hyperalkaline seepage and the carbonate deposits can be measures of the grout-treated foundation rock durability.
Mutations continue to accumulate within the SARS-CoV-2 genome, and the ongoing epidemic has shown no signs of ending. It is critical to predict problematic mutations that may arise in clinical ...environments and assess their properties in advance to quickly implement countermeasures against future variant infections. In this study, we identified mutations resistant to remdesivir, which is widely administered to SARS-CoV-2-infected patients, and discuss the cause of resistance. First, we simultaneously constructed eight recombinant viruses carrying the mutations detected in in vitro serial passages of SARS-CoV-2 in the presence of remdesivir. We confirmed that all the mutant viruses didn't gain the virus production efficiency without remdesivir treatment. Time course analyses of cellular virus infections showed significantly higher infectious titers and infection rates in mutant viruses than wild type virus under treatment with remdesivir. Next, we developed a mathematical model in consideration of the changing dynamic of cells infected with mutant viruses with distinct propagation properties and defined that mutations detected in in vitro passages canceled the antiviral activities of remdesivir without raising virus production capacity. Finally, molecular dynamics simulations of the NSP12 protein of SARS-CoV-2 revealed that the molecular vibration around the RNA-binding site was increased by the introduction of mutations on NSP12. Taken together, we identified multiple mutations that affected the flexibility of the RNA binding site and decreased the antiviral activity of remdesivir. Our new insights will contribute to developing further antiviral measures against SARS-CoV-2 infection.
Testing and diagnosis for COVID-19 SADAMASU, Kenji; YOSHIMURA, Kazuhisa
Journal of the National Institute of Public Health,
2022/10/31, Volume:
71, Issue:
4
Journal Article
Open access
Nucleic acid amplification tests for coronavirus diseases (COVID-19) were nearly established by the end of January 2020, mainly at regional Public Health Laboratories (PHLs) nationwide. Initially, ...the nucleic acid amplification test was a combination of conventional PCR and sequencing, in accordance with the pathogen detection manual of the National Institute of Infectious Diseases (NIID). However, this was soon changed to a real-time PCR method (NIID method), and test reagents were distributed by the NIID. In order to cope with the further increase in the number of tests, private laboratories began testing for novel coronaviruses in March, and PHLs cooperated with the launch of testing by private laboratories. Subsequently, a large variety of test reagents that replaced the NIID method were approved by the Ministry of Health, Labour and Welfare as in vitro diagnostic products.In December 2020, highly infectious variants of SARS-CoV-2 emerged, and the PHL also became involved in screening tests and genome analysis to identify and analyze the alpha strain and other strains specified as Variants of Concern (VOC) by the World Health Organization (WHO). The epidemic that followed was characterized by a replacement of the initial variant with new variants, and the PHL also added SARS-CoV-2 whole-genome analysis using next-generation sequencers (NGS) and variant surveillance via real-time PCR to its work. This manuscript outlines the events of the past three years, including the establishment of Nucleic acid amplification tests at PHLs and our response to new variants.
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Hybrid molecules containing small CD4 mimics and gp41-C-terminal heptad repeat (CHR)-related peptides have been developed. A YIR-821 derivative was adopted as a CD4 mimic, which ...inhibits the interaction of gp120 with CD4. SC-peptides, SC34 and SC22EK, were also used as CHR-related peptides, which inhibit the interaction between the N-terminal heptad repeat (NHR) and CHR and thereby membrane fusion. Therefore, these hybrid molecules have dual-targets of gp120 and gp41. In the synthesis of the hybrid molecules of CD4 mimic-SC-peptides with different lengths of linkers, two conjugating methods, Cu-catalyzed azide-alkyne cycloaddition and direct cysteine alkylation, were performed. The latter reaction caused simpler operation procedures and higher synthetic yields than the former. The synthesized hybrid molecules of CD4 mimic-SC22EK have significantly higher anti-HIV activity than each sole agent. The present data should be useful in the future design of anti-HIV agents as dual-target entry inhibitors.
CCR5 is a member of the G-protein coupled receptor family that serves as an essential co-receptor for cellular entry of R5-tropic HIV-1, and is a validated target for therapeutics against HIV-1 ...infections. In the present study, we designed and synthesized a series of novel small CCR5 inhibitors and evaluated their antiviral activity. GRL-117C inhibited the replication of wild-type R5-HIV-1 with a sub-nanomolar IC
value. These derivatives retained activity against vicriviroc-resistant HIV-1s, but did not show activity against maraviroc (MVC)-resistant HIV-1. Structural modeling indicated that the binding of compounds to CCR5 occurs in the hydrophobic cavity of CCR5 under the second extracellular loop, and amino acids critical for their binding were almost similar with those of MVC, which explains viral cross-resistance with MVC. On the other hand, one derivative, GRL-10018C, less potent against HIV-1, but more potent in inhibiting CC-chemokine binding, occupied the upper region of the binding cavity with its bis-THF moiety, presumably causing greater steric hindrance with CC-chemokines. Recent studies have shown additional unique features of certain CCR5 inhibitors such as immunomodulating properties and HIV-1 latency reversal properties, and thus, continuous efforts in developing new CCR5 inhibitors with unique binding profiles is necessary.
The circulation of chromium at naturally occurring concentration levels (i.e., 1μgdm−3 or lower) was examined using solid-phase spectrophotometry and inductively coupled plasma-mass spectrophotometry ...(ICP-MS) to determine the Cr(VI) and Cr(Total) concentrations, respectively. Natural water and stream sediments were collected from areas with various types of geologic features, such as metamorphic rocks, volcanic rocks and limestone in Japan and Indonesia. Cr(VI) was predominant in weakly alkaline natural waters, and the Cr(III) concentration was less than 1μgdm−3, which was considerably lower than that expected based on the solubility of Cr(OH)3. The dissolution of chromium in natural water was described by the leaching of Cr(VI) from Cr(III)-containing minerals under oxic conditions. The Cr(VI) concentration in a solution that was in contact with chromite, FeCr2O4, linearly increased with the reaction time. The results indicated that under oxic conditions at PO2=0.21atm, the leaching rate of Cr(VI) was pseudo zero-order at a fixed pH and was higher in alkaline than in acidic solutions. The removal of Cr from natural waters was due to the reduction of Cr(VI) to Cr(III) by organic matter, such as humic substances, as well as to the adsorption of Cr(III) onto suspended matter and river sediments. The reduction of Cr(VI) to Cr(III) followed the equation −dCr(VI)/dt=H+aCr(VI)DOC with a=0 at pH<4 and a=−1 at pH>4.5. The removal of Cr(III) by river sediments and/or suspended particulate matter was rapid and the adsorbability of Cr(III) was dependent on pH, which suggests that the active species were Cr(OH)2+ and Cr(OH)3. Schematic models of the circulation of dissolved chromium in natural water were proposed under acidic and alkaline conditions.
•Cr speciation in natural waters is studied using solid-phase spectrophotometry.•We examine the addition mechanism of Cr into natural water under oxic conditions.•The removal process of Cr is described using the reduction–adsorption data.•Schematic models of Cr circulation in natural water are postulated.
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