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1.
Cochrane Database Syst Rev ; 8: CD013207, 2021 08 12.
Article in English | MEDLINE | ID: covidwho-1813441

ABSTRACT

BACKGROUND: The standard method of diagnosing HIV in infants and children less than 18 months is with a nucleic acid amplification test reverse transcriptase polymerase chain reaction test (NAT RT-PCR) detecting viral ribonucleic acid (RNA). Laboratory testing using the RT-PCR platform for HIV infection is limited by poor access, logistical support, and delays in relaying test results and initiating therapy in low-resource settings. The use of rapid diagnostic tests at or near the point-of-care (POC) can increase access to early diagnosis of HIV infection in infants and children less than 18 months of age and timely initiation of antiretroviral therapy (ART). OBJECTIVES: To summarize the diagnostic accuracy of point-of-care nucleic acid-based testing (POC NAT) to detect HIV-1/HIV-2 infection in infants and children aged 18 months or less exposed to HIV infection. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (until 2 February 2021), MEDLINE and Embase (until 1 February 2021), and LILACS and Web of Science (until 2 February 2021) with no language or publication status restriction. We also searched conference websites and clinical trial registries, tracked reference lists of included studies and relevant systematic reviews, and consulted experts for potentially eligible studies. SELECTION CRITERIA: We defined POC tests as rapid diagnostic tests conducted at or near the patient site. We included any primary study that compared the results of a POC NAT to a reference standard of laboratory NAT RT-PCR or total nucleic acid testing to detect the presence or absence of HIV infection denoted by HIV viral nucleic acids in infants and children aged 18 months or less who were exposed to HIV-1/HIV-2 infection. We included cross-sectional, prospective, and retrospective study designs and those that provided sufficient data to create the 2 × 2 table to calculate sensitivity and specificity. We excluded diagnostic case control studies with healthy controls. DATA COLLECTION AND ANALYSIS: We extracted information on study characteristics using a pretested standardized data extraction form. We used the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) tool to assess the risk of bias and applicability concerns of the included studies. Two review authors independently selected and assessed the included studies, resolving any disagreements by consensus. The unit of analysis was the participant. We first conducted preliminary exploratory analyses by plotting estimates of sensitivity and specificity from each study on forest plots and in receiver operating characteristic (ROC) space. For the overall meta-analyses, we pooled estimates of sensitivity and specificity using the bivariate meta-analysis model at a common threshold (presence or absence of infection). MAIN RESULTS: We identified a total of 12 studies (15 evaluations, 15,120 participants). All studies were conducted in sub-Saharan Africa. The ages of included infants and children in the evaluations were as follows: at birth (n = 6), ≤ 12 months (n = 3), ≤ 18 months (n = 5), and ≤ 24 months (n = 1). Ten evaluations were field evaluations of the POC NAT test at the point of care, and five were laboratory evaluations of the POC NAT tests.The POC NAT tests evaluated included Alere q HIV-1/2 Detect qualitative test (recently renamed m-PIMA q HIV-1/2 Detect qualitative test) (n = 6), Xpert HIV-1 qualitative test (n = 6), and SAMBA HIV-1 qualitative test (n = 3). POC NAT pooled sensitivity and specificity (95% confidence interval (CI)) against laboratory reference standard tests were 98.6% (96.1 to 99.5) (15 evaluations, 1728 participants) and 99.9% (99.7 to 99.9) (15 evaluations, 13,392 participants) in infants and children ≤ 18 months. Risk of bias in the included studies was mostly low or unclear due to poor reporting. Five evaluations had some concerns for applicability for the index test, as they were POC tests evaluated in a laboratory setting, but there was no difference detected between settings in sensitivity (-1.3% (95% CI -4.1 to 1.5)); and specificity results were similar. AUTHORS' CONCLUSIONS: For the diagnosis of HIV-1/HIV-2 infection, we found the sensitivity and specificity of POC NAT tests to be high in infants and children aged 18 months or less who were exposed to HIV infection.


Subject(s)
HIV Infections/diagnosis , HIV-1/genetics , HIV-2/genetics , Point-of-Care Testing , Polymerase Chain Reaction/methods , Cross-Sectional Studies , Female , HIV-1/isolation & purification , HIV-2/isolation & purification , Humans , Infant , Infant, Newborn , Male , Reverse Transcriptase Polymerase Chain Reaction , Sensitivity and Specificity
2.
Molecules ; 27(5)2022 Feb 24.
Article in English | MEDLINE | ID: covidwho-1780062

ABSTRACT

Diseases caused by viruses are a global threat, resulting in serious medical and social problems for humanity. They are the main contributors to many minor and major outbreaks, epidemics, and pandemics worldwide. Over the years, medicinal plants have been used as a complementary treatment in a range of diseases. In this sense, this review addresses promising antiviral plants from Marajó island, a part of the Amazon region, which is known to present a very wide biodiversity of medicinal plants. The present review has been limited to articles and abstracts available in Scopus, Web of Science, Science Direct, Scielo, PubMed, and Google Scholar, as well as the patent offices in Brazil (INPI), United States (USPTO), Europe (EPO) and World Intellectual Property Organization (WIPO). As a result, some plants from Marajó island were reported to have actions against HIV-1,2, HSV-1,2, SARS-CoV-2, HAV and HBV, Poliovirus, and influenza. Our major conclusion is that plants of the Marajó region show promising perspectives regarding pharmacological potential in combatting future viral diseases.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Plant Extracts/chemistry , Plants, Medicinal/chemistry , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , Brazil , COVID-19/virology , HIV-1/drug effects , Hepatitis A virus/drug effects , Herpesvirus 1, Human/drug effects , Humans , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Plants, Medicinal/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification
3.
Trials ; 23(1): 263, 2022 Apr 05.
Article in English | MEDLINE | ID: covidwho-1779666

ABSTRACT

BACKGROUND: Antiretroviral therapy (ART) has led to dramatic improvements in survival for people living with HIV, but is unable to cure infection, or induce viral control off therapy. Designing intervention trials with novel agents with the potential to confer a period of HIV remission without ART remains a key scientific and community goal. We detail the rationale, design, and outcomes of a randomised, placebo-controlled trial of two HIV-specific long-acting broadly neutralising antibodies (bNAbs): 3BNC117-LS and 10-1074-LS, which target CD4 binding site and V3 loop respectively, on post-treatment viral control. METHODS: RIO is a randomised, placebo-controlled, double-blinded prospective phase II study. Eligible individuals will have started ART within 3 months of primary HIV infection and have viral sequences that appear to be sensitive to both bNAbs. It will randomise 72 eligible participants 1:1 to the following arms via a two-stage design. In Stage 1, arm A participants are given dual long-acting (LS-variants) bNAbs infusions, followed by intensively monitored Analytical Treatment Interruption (ATI) (n = 36); in arm B, participants receive placebo infusions followed by ATI. The primary endpoint will be time to viral rebound within 36 weeks after ATI. Upon viral rebound, the participant and researcher are unblinded. Participants in arm A recommence ART and complete the study. Participants in arm B are invited to restart ART and enroll into Stage 2 where they will receive open-label LS bNAbs, followed by a second ATI 24 weeks after. Secondary and exploratory endpoints include adverse events, time to undetectable viraemia after restarting ART, immunological markers, HIV proviral DNA, serum bNAb concentrations in blood, bNAb resistance at viral rebound, and quality of life measures. DISCUSSION: The two-stage design was determined in collaboration with community involvement. This design allows all participants the option to receive bNAbs. It also tests the hypothesis that bNAbs may drive sustained HIV control beyond the duration of detectable bNAb concentrations. Community representatives were involved at all stages. This included the two-stage design, discussion on the criteria to restart ART, frequency of monitoring visits off ART, and reducing the risk of onward transmission to HIV-negative partners. It also included responding to the challenges of COVID-19. TRIAL REGISTRATION: The protocol is registered on Clinical. TRIALS: gov and EudraCT and has approval from UK Ethics and MHRA.


Subject(s)
COVID-19 , HIV Infections , HIV-1 , Broadly Neutralizing Antibodies , Clinical Trials, Phase II as Topic , Community Participation , HIV Antibodies , HIV Infections/diagnosis , HIV Infections/drug therapy , Humans , Prospective Studies , Quality of Life , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome
6.
Front Public Health ; 10: 820727, 2022.
Article in English | MEDLINE | ID: covidwho-1776016

ABSTRACT

Aim: To perform a systematic review to describe the available findings on clinical outcomes in HIV-1 and HTLV-1/HTLV-2 co-infected individuals since 1995. Design: This Systematic Review used PECO criteria follow by PRISMA reporting guidelines and registered as CRD42021279062 (Prospero database). The Newcastle-Ottawa Scale assessed the methodological quality of included studies. Data Collection and Analysis: A systematical search in PubMed/MEDLINE, Embase, Web of Sciences databases for cross-sectional, case-control, or cohort studies design to identify clinical and laboratorial outcomes related to HIV-1 and HTLV-1/2 coinfection. Search strategy: [("HIV-1" AND "HTLV-1" OR "HTLV-2") AND ("Coinfection") AND (1990/01/01:2021/12/31[Date- Publication])]. Results: A total of 15 articles were included on this systematic review describing data of 2,566 mono and coinfected patients, 58% male, with mean age was 35.7 ± 5.7 years. HIV-1 and HTLV-1 coinfected patients were more likely to had shorter survival and faster progression to death or mortality than monoinfected ones. Coinfected had higher CD4 cell counts and less likelihood of ART use. In addition, higher frequency of diseases like ichthyosis (22.2 vs. 6.8%), scabies (18.6 vs. 0%), candidiasis (42 vs. 12%), Strongyloidiasis (15.4 vs. 2%) and neurological manifestations like encephalopathy, peripheral neuropathy and HAM/TSP were more frequently reported in coinfected patients. Conclusions: HIV-1 and HTLV-1 coinfection and HIV-1 and HTLV-1 /2 triple coinfection were related to shorter survival, higher mortality rate, and faster progression to death, while coinfection by HIV-1/HTLV-2 seems to have neutral association with longer survival, slower AIDS progression, and lower mortality rate. The available evidence indicates an urgent need for prevention and control measures, including screening, diagnosis, and treatment of HIV-1 and HTLV-1/2 coinfected patients. Test-and-treat strategy for patients living with HIV in areas endemic for HTLV infection is mandatory, to avoid the risks of delayed therapy and death for coinfected patients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42021279062.


Subject(s)
Coinfection , HIV Infections , HTLV-I Infections , HTLV-II Infections , Adult , Coinfection/epidemiology , Cross-Sectional Studies , Female , HIV Infections/diagnosis , HIV Infections/epidemiology , HIV-1 , HTLV-I Infections/diagnosis , HTLV-I Infections/epidemiology , HTLV-II Infections/diagnosis , HTLV-II Infections/epidemiology , Human T-lymphotropic virus 1 , Human T-lymphotropic virus 2 , Humans , Male
7.
Viruses ; 14(3)2022 03 18.
Article in English | MEDLINE | ID: covidwho-1765956

ABSTRACT

Gag virus-like particles (VLPs) are promising vaccine candidates against infectious diseases. VLPs are generally produced using the insect cell/baculovirus expression vector system (BEVS), or in mammalian cells by plasmid DNA transient gene expression (TGE). However, VLPs produced with the insect cell/BEVS are difficult to purify and might not display the appropriate post-translational modifications, whereas plasmid DNA TGE approaches are expensive and have a limited scale-up capability. In this study, the production of Gag VLPs with the BacMam expression system in a suspension culture of HEK293 cells is addressed. The optimal conditions of multiplicity of infection (MOI), viable cell density (VCD) at infection, and butyric acid (BA) concentration that maximize cell transduction and VLP production are determined. In these conditions, a maximum cell transduction efficiency of 91.5 ± 1.1%, and a VLP titer of 2.8 ± 0.1 × 109 VLPs/mL are achieved. Successful VLP generation in transduced HEK293 cells is validated using super-resolution fluorescence microscopy, with VLPs produced resembling immature HIV-1 virions and with an average size comprised in the 100-200 nm range. Additionally, evidence that BacMam transduction occurs via different pathways including dynamin-mediated endocytosis and macropinocytosis is provided. This work puts the basis for future studies aiming at scaling up the BacMam baculovirus system as an alternative strategy for VLP production.


Subject(s)
HIV-1 , Viruses, Unclassified , Animals , Baculoviridae/genetics , DNA , HEK293 Cells , HIV-1/genetics , Humans , Mammals , Virion/genetics , Viruses, Unclassified/genetics
8.
Viruses ; 14(3)2022 03 21.
Article in English | MEDLINE | ID: covidwho-1753693

ABSTRACT

Only limited data are available regarding the immunogenicity of the BNT162b2 mRNA vaccine in HIV-1+ patients. Therefore, we investigated the humoral immune response after BNT162b2-mRNA vaccination or SARS-CoV-2 infection in HIV-1+ patients on antiretroviral therapy compared to HIV-1-uninfected subjects. Serum and saliva samples were analysed by SARS-CoV-2 spike-specific IgG and IgA ELISAs and a surrogate neutralization assay. While all subjects developed anti-spike IgG and IgA and neutralizing antibodies in serum after two doses of BNT162b2 mRNA vaccine, the HIV-1+ subjects displayed significantly lower neutralizing capacity and anti-spike IgA in serum compared to HIV-1-uninfected subjects. Serum levels of anti-spike IgG and neutralizing activity were significantly higher in vaccinees compared to SARS-CoV-2 convalescents irrespective of HIV-1 status. Among SARS-CoV-2 convalescents, there was no significant difference in spike-specific antibody response between HIV-1+ and uninfected subjects. In saliva, anti-spike IgG and IgA antibodies were detected both in vaccinees and convalescents, albeit at lower frequencies compared to the serum and only rarely with detectable neutralizing activity. In summary, our study demonstrates that the BNT162b2 mRNA vaccine induces SARS-CoV-2-specific antibodies in HIV-1-infected patients on antiretroviral therapy, however, lower vaccine induced neutralization activity indicates a lower functionality of the humoral vaccine response in HIV-1+ patients.


Subject(s)
COVID-19 , HIV-1 , Viral Vaccines , COVID-19/prevention & control , Humans , RNA, Messenger/genetics , SARS-CoV-2 , Vaccination , Vaccines, Synthetic
9.
Cell Rep ; 38(11): 110514, 2022 03 15.
Article in English | MEDLINE | ID: covidwho-1739598

ABSTRACT

The success of nucleoside-modified mRNAs in lipid nanoparticles (mRNA-LNP) as COVID-19 vaccines heralded a new era of vaccine development. For HIV-1, multivalent envelope (Env) trimer protein nanoparticles are superior immunogens compared with trimers alone for priming of broadly neutralizing antibody (bnAb) B cell lineages. The successful expression of complex multivalent nanoparticle immunogens with mRNAs has not been demonstrated. Here, we show that mRNAs can encode antigenic Env trimers on ferritin nanoparticles that initiate bnAb precursor B cell expansion and induce serum autologous tier 2 neutralizing activity in bnAb precursor VH + VL knock-in mice. Next-generation sequencing demonstrates acquisition of critical mutations, and monoclonal antibodies that neutralize heterologous HIV-1 isolates are isolated. Thus, mRNA-LNP can encode complex immunogens and may be of use in design of germline-targeting and sequential boosting immunogens for HIV-1 vaccine development.


Subject(s)
AIDS Vaccines , COVID-19 , HIV-1 , Nanoparticles , Animals , Antibodies, Monoclonal , Antibodies, Neutralizing , COVID-19 Vaccines , Epitopes , Ferritins/genetics , HIV Antibodies , Humans , Liposomes , Mice , RNA, Messenger , env Gene Products, Human Immunodeficiency Virus/genetics
10.
Front Immunol ; 12: 794638, 2021.
Article in English | MEDLINE | ID: covidwho-1731769

ABSTRACT

CCR5 plays a central role in infectious disease, host defense, and cancer progression, thereby making it an ideal target for therapeutic development. Notably, CCR5 is the major HIV entry co-receptor, where its surface density correlates with HIV plasma viremia. The level of CCR5 receptor occupancy (RO) achieved by a CCR5-targeting therapeutic is therefore a critical predictor of its efficacy. However, current methods to measure CCR5 RO lack sensitivity, resulting in high background and overcalculation. Here, we report on two independent, flow cytometric methods of calculating CCR5 RO using the anti-CCR5 antibody, Leronlimab. We show that both methods led to comparable CCR5 RO values, with low background on untreated CCR5+CD4+ T cells and sensitive measurements of occupancy on both blood and tissue-resident CD4+ T cells that correlated longitudinally with plasma concentrations in Leronlimab-treated macaques. Using these assays, we found that Leronlimab stabilized cell surface CCR5, leading to an increase in the levels of circulating and tissue-resident CCR5+CD4+ T cells in vivo in Leronlimab-treated macaques. Weekly Leronlimab treatment in a chronically SIV-infected macaque led to increased CCR5+CD4+ T cells levels and fully suppressed plasma viremia, both concomitant with full CCR5 RO on peripheral blood CD4+ T cells, demonstrating that CCR5+CD4+ T cells were protected from viral replication by Leronlimab binding. Finally, we extended these results to Leronlimab-treated humans and found that weekly 700 mg Leronlimab led to complete CCR5 RO on peripheral blood CD4+ T cells and a statistically significant increase in CCR5+CD4+ T cells in peripheral blood. Collectively, these results establish two RO calculation methods for longitudinal monitoring of anti-CCR5 therapeutic antibody blockade efficacy in both macaques and humans, demonstrate that CCR5+CD4+ T cell levels temporarily increase with Leronlimab treatment, and facilitate future detailed investigations into the immunological impacts of CCR5 inhibition in multiple pathophysiological processes.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , CD4-Positive T-Lymphocytes/immunology , COVID-19/drug therapy , Flow Cytometry/methods , HIV Antibodies/therapeutic use , HIV Infections/drug therapy , HIV-1/physiology , Receptors, CCR5/metabolism , SARS-CoV-2/physiology , Simian Acquired Immunodeficiency Syndrome/drug therapy , Simian Immunodeficiency Virus/physiology , Animals , CD4 Lymphocyte Count , Female , Humans , Primates , Protein Binding , Receptors, CCR5/immunology , Treatment Outcome
11.
Front Immunol ; 12: 820126, 2021.
Article in English | MEDLINE | ID: covidwho-1715000

ABSTRACT

This study aims to assess the immunological response and impact on virological control of the mRNA vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among people living with HIV (PLWH). In this single-center observational study, all PLWH were offered vaccination with mRNA1273 or BNT162b2. Both anti-N and anti-S1-receptor binding domain (RBD) antibodies were measured together with HIV-1 RNA levels after the first dose (M0) and then at 1 (M1), 2 (M2) and 6 (M6) months later. A total of 131 individuals (median age: 54 years [IQR: 47.0-60.5]; male: 70.2%; median baseline CD4 T-cell: 602/µl [IQR 445.0-825.5]; median nadir CD4 T-cells 223/µl [IQR 111.0-330.0]) were included. All participants were positive for anti-RBD antibodies at 30 days, 60 days and 6 months after the first dose, with no statistical difference between those with HIV-1 RNA below or >20 copies/ml. HIV-1 RNA data were collected for 128 patients at baseline and 30 days after the first dose; for 124 individuals, 30 days after the second dose; and for 83 patients, 6 months after the first dose. Nineteen (14.8%) of 128 had detectable HIV-1 RNA (>20 copies/ml) at M0, 13/128 (10.2%) at M1 (among which 5 were newly detectable), 15/124 (12.1%) at M2 (among which 5 were newly detectable), and 8/83 (9.6%) at M6. No serious adverse effects were reported. All participants elicited antibodies after two doses of mRNA vaccines, with only a minor impact on HIV-1 RNA levels over a 6-month period.


Subject(s)
/immunology , CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , HIV Infections/immunology , HIV-1/physiology , RNA, Viral/analysis , SARS-CoV-2/physiology , Adult , Aged , Antibodies, Viral/blood , Antibody Formation , Coronavirus Nucleocapsid Proteins/immunology , Female , Humans , Immunity, Heterologous , Male , Middle Aged , Phosphoproteins/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination
12.
Cell Host Microbe ; 30(2): 154-162.e5, 2022 02 09.
Article in English | MEDLINE | ID: covidwho-1708092

ABSTRACT

Characterizing SARS-CoV-2 evolution in specific geographies may help predict properties of the variants that come from these regions. We mapped neutralization of a SARS-CoV-2 strain that evolved over 6 months from ancestral virus in a person with advanced HIV disease in South Africa; this person was infected prior to emergence of the Beta and Delta variants. We longitudinally tracked the evolved virus and tested it against self-plasma and convalescent plasma from ancestral, Beta, and Delta infections. Early virus was similar to ancestral, but it evolved a multitude of mutations found in Omicron and other variants. It showed substantial but incomplete Pfizer BNT162b2 escape, weak neutralization by self-plasma, and despite pre-dating Delta, it also showed extensive escape of Delta infection-elicited neutralization. This example is consistent with the notion that SARS-CoV-2 evolving in individual immune-compromised hosts, including those with advanced HIV disease, may gain immune escape of vaccines and enhanced escape of Delta immunity, and this has implications for vaccine breakthrough and reinfections.


Subject(s)
Antibodies, Neutralizing/blood , HIV Infections/pathology , Immune Evasion/immunology , Immunogenicity, Vaccine/immunology , SARS-CoV-2/immunology , Adult , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19 Vaccines/immunology , Cell Line , Chlorocebus aethiops , Female , HIV-1/immunology , Humans , Immunocompromised Host/immunology , Neutralization Tests , SARS-CoV-2/isolation & purification , South Africa , Vaccination , Vero Cells
13.
Proc Natl Acad Sci U S A ; 119(9)2022 03 01.
Article in English | MEDLINE | ID: covidwho-1699265

ABSTRACT

There are genetic risk factors that influence the outcome of COVID-19 [COVID-19 Host Genetics Initiative, Nature 600, 472-477 (2021)]. The major genetic risk factor for severe COIVD-19 resides on chromosome 3 and is inherited from Neandertals [H. Zeberg, S. Pääbo, Nature 587, 610-612 (2020)]. The risk-associated DNA segment modulates the expression of several chemokine receptors, among them CCR5, a coreceptor for HIV which is down-regulated in carriers of the COVID-19 risk haplotype. Here I show that carriers of the risk variant have an ∼27% lower risk of HIV infection.


Subject(s)
COVID-19/genetics , Chromosomes, Human, Pair 3/genetics , HIV Infections/genetics , HIV-1 , Haplotypes , SARS-CoV-2 , COVID-19/prevention & control , HIV Infections/prevention & control , Humans , Patient Acuity , Risk Factors
14.
Virol J ; 19(1): 29, 2022 02 10.
Article in English | MEDLINE | ID: covidwho-1690906

ABSTRACT

Ultraviolet (UV) light has previously been established as useful method of disinfection, with demonstrated efficacy to inactivate a broad range of microorganisms. The advent of ultraviolet light-emitting diodes provides advantages in ease of disinfection, in that there can be delivery of germicidal UV with the same light unit that delivers standard white light to illuminate a room. Herein we demonstrate the efficacy and feasibility of ultraviolet light-emitting diodes as a means of decontamination by inactivating two distinct virus models, human coronavirus 229E and human immunodeficiency virus. Importantly, the same dose of ultraviolet light that inactivated human viruses also elicited complete inactivation of ultraviolet-resistant bacterial spores (Bacillus pumilus), a gold standard for demonstrating ultraviolet-mediated disinfection. This work demonstrates that seconds of ultraviolet light-emitting diodes (UV-LED) exposure can inactivate viruses and bacteria, highlighting that UV-LED could be a useful and practical tool for broad sanitization of public spaces.


Subject(s)
Coronavirus 229E, Human , Disinfection , HIV-1 , Ultraviolet Rays , Virus Inactivation/radiation effects , Coronavirus 229E, Human/radiation effects , Disinfection/methods , HIV-1/radiation effects , Humans
15.
J Infect Dis ; 225(5): 856-861, 2022 Mar 02.
Article in English | MEDLINE | ID: covidwho-1666006

ABSTRACT

We tested the combination of a broadly neutralizing HIV antibody with the latency reversal agent vorinostat (VOR). Eight participants received 2 month-long cycles of VRC07-523LS with VOR. Low-level viremia, resting CD4+ T-cell-associated HIV RNA (rca-RNA) was measured, and intact proviral DNA assay (IPDA) and quantitative viral outgrowth assay (QVOA) were performed at baseline and posttreatment. In 3 participants, IPDA and QVOA declines were accompanied by significant declines of rca-RNA. However, no IPDA or QVOA declines clearly exceeded assay variance or natural decay. Increased resistance to VRC07-523LS was not observed. This combination therapy did not reduce viremia or the HIV reservoir. Clinical Trials Registration. NCT03803605.


Subject(s)
HIV Infections , HIV-1 , Broadly Neutralizing Antibodies , CD4-Positive T-Lymphocytes , HIV-1/genetics , Humans , Viremia/drug therapy , Virus Latency , Vorinostat/therapeutic use
16.
Acc Chem Res ; 55(4): 565-578, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1655394

ABSTRACT

Modified nucleosides show therapeutic promise for antiviral therapies. However, issues including the emergence of drug resistance, toxicity, and coinfections have posed new challenges for nucleoside-based antiviral drug discovery, particularly in the era of the coronavirus disease 2019 (COVID-19) pandemic. Chemical manipulation could impact the antiviral potency, safety, and drug resistance of nucleosides. Generally, modified nucleosides are difficult to recognize by intracellular important enzymes as substrates and thus exhibit low toxicity. 4'-Modified nucleosides represent an important subclass of modified nucleosides for antiviral therapies. To prevent the occurrence of drug resistance, 4'-modified nucleosides should have 3'-OH, which should also be chemically unreactive for proviral DNA biosynthesis. The absence of 3'-OH may explain the occurrence of drug resistance for censavudine. The introduction of 4'-substituents improves enzymatic and acidic stability and makes the nucleosides more lipophilic, thus improving cell permeability and bioavailability. Steric hindrance between the 4'-substituent and 3'-OH changes the furanose conformation to the 3'-endo type, in which the oxygen lone pair on the furanose ring could not form an oxocarbonium ion for glycolysis. Currently, seven 4'-modified nucleoside drug candidates such as azvudine (also known as FNC), islatravir, censavudine, balapiravir, lumicitabine, AL-335, and 4-azidothymidine have progressed into clinical stages for treating viral infections. Of note, FNC was officially approved by NMPA in July 2021 for use in adult patients with high HIV-1 virus loads (nos. H20210035 and H20210036), providing an alternative therapeutic for patients with HIV-1. The long-term cellular retention of FNC suggests its potential as a long-lasting pre-exposure prophylaxis (PrEP) agent for preventing HIV-1 infection. Mechanistically, FNC not only inhibited HIV-1 reverse transcription and replication but also restored A3G expression in peripheral blood CD4+ T cells in HIV-1 patients receiving FNC. The 4'-azido group in azvudine stabilizes the 3'-C-endo (north) conformation by steric effects and the formation of an intramolecular hydrogen bond with the 3'-OH group, thus decreasing the nucleophilicity of 3'-OH. The north conformation may also enhance the phosphorylation efficiency of FNC by cellular kinases. Encouragingly, FNC, islatravir, and balapiravir show promise for the treatment of coronaviruses, of which FNC has advanced to phase 3 clinical trials in different countries to treat patients with COVID-19 (clinical trial numbers: NCT04668235 and NCT04425772). FNC cured the COVID-19 disease in almost all patients and showed better therapeutic efficacy than remdesivir. In this Account, we provide an overview of 4'-modified nucleoside analogs in clinical stages for antiviral therapies, highlighting the drug discovery strategies, structure-activity relationship studies, and preclinical/clinical studies and also give our perspectives on nucleoside-based antiviral drug discovery.


Subject(s)
COVID-19 , HIV-1 , Antiviral Agents/pharmacology , Drug Discovery , Humans , Nucleosides , SARS-CoV-2
17.
Molecules ; 27(1)2022 Jan 04.
Article in English | MEDLINE | ID: covidwho-1613911

ABSTRACT

When developing drugs against SARS-CoV-2, it is important to consider the characteristics of patients with different co-morbidities. People infected with HIV-1 are a particularly vulnerable group, as they may be at a higher risk than the general population of contracting COVID-19 with clinical complications. For such patients, drugs with a broad spectrum of antiviral activity are of paramount importance. Glycyrrhizinic acid (Glyc) and its derivatives are promising biologically active compounds for the development of such broad-spectrum antiviral agents. In this work, derivatives of Glyc obtained by acylation with nicotinic acid were investigated. The resulting preparation, Glycyvir, is a multi-component mixture containing mainly mono-, di-, tri- and tetranicotinates. The composition of Glycyvir was characterized by HPLC-MS/MS and its toxicity assessed in cell culture. Antiviral activity against three strains of SARS-CoV-2 was tested in vitro on Vero E6 cells by MTT assay. Glycyvir was shown to inhibit SARS-CoV-2 replication in vitro (IC502-8 µM) with an antiviral activity comparable to the control drug Remdesivir. In addition, Glycyvir exhibited marked inhibitory activity against HIV pseudoviruses of subtypes B, A6 and the recombinant form CRF63_02A (IC50 range 3.9-27.5 µM). The time-dependence of Glycyvir inhibitory activity on HIV pseudovirus infection of TZM-bl cells suggested that the compound interfered with virus entry into the target cell. Glycyvir is a promising candidate as an agent with low toxicity and a broad spectrum of antiviral action.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Glycyrrhizic Acid/chemistry , HIV Infections/drug therapy , HIV-1/drug effects , SARS-CoV-2/drug effects , Virus Replication , Animals , Antiviral Agents/chemical synthesis , COVID-19/virology , Chlorocebus aethiops , HIV Infections/virology , HeLa Cells , Humans , In Vitro Techniques , Vero Cells
18.
Signal Transduct Target Ther ; 7(1): 7, 2022 01 04.
Article in English | MEDLINE | ID: covidwho-1606287

ABSTRACT

Activation-induced cytidine deaminase (AID) initiates class-switch recombination and somatic hypermutation (SHM) in antibody genes. Protein expression and activity are tightly controlled by various mechanisms. However, it remains unknown whether a signal from the extracellular environment directly affects the AID activity in the nucleus where it works. Here, we demonstrated that a deubiquitinase USP10, which specifically stabilizes nuclear AID protein, can translocate into the nucleus after AKT-mediated phosphorylation at its T674 within the NLS domain. Interestingly, the signals from BCR and TLR1/2 synergistically promoted this phosphorylation. The deficiency of USP10 in B cells significantly decreased AID protein levels, subsequently reducing neutralizing antibody production after immunization with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or human immunodeficiency virus type 1 (HIV-1) nanoparticle vaccines. Collectively, we demonstrated that USP10 functions as an integrator for both BCR and TLR signals and directly regulates nuclear AID activity. Its manipulation could be used for the development of vaccines and adjuvants.


Subject(s)
AIDS Vaccines/immunology , B-Cell Activating Factor/immunology , COVID-19 Vaccines/immunology , Cytidine Deaminase/immunology , HIV-1/immunology , Nanoparticles , SARS-CoV-2/immunology , Signal Transduction/immunology , Ubiquitin Thiolesterase/immunology , Ubiquitination/immunology , AIDS Vaccines/genetics , Animals , B-Cell Activating Factor/genetics , COVID-19 Vaccines/genetics , Cytidine Deaminase/genetics , HEK293 Cells , HIV-1/genetics , Humans , Mice , Mice, Knockout , SARS-CoV-2/genetics , Signal Transduction/genetics , Ubiquitin Thiolesterase/genetics
19.
Nucleic Acids Res ; 49(17): e102, 2021 09 27.
Article in English | MEDLINE | ID: covidwho-1594917

ABSTRACT

Rapidly evolving RNA viruses continuously produce minority haplotypes that can become dominant if they are drug-resistant or can better evade the immune system. Therefore, early detection and identification of minority viral haplotypes may help to promptly adjust the patient's treatment plan preventing potential disease complications. Minority haplotypes can be identified using next-generation sequencing, but sequencing noise hinders accurate identification. The elimination of sequencing noise is a non-trivial task that still remains open. Here we propose CliqueSNV based on extracting pairs of statistically linked mutations from noisy reads. This effectively reduces sequencing noise and enables identifying minority haplotypes with the frequency below the sequencing error rate. We comparatively assess the performance of CliqueSNV using an in vitro mixture of nine haplotypes that were derived from the mutation profile of an existing HIV patient. We show that CliqueSNV can accurately assemble viral haplotypes with frequencies as low as 0.1% and maintains consistent performance across short and long bases sequencing platforms.


Subject(s)
Algorithms , Computational Biology/methods , Haplotypes , High-Throughput Nucleotide Sequencing/methods , RNA Virus Infections/diagnosis , RNA Viruses/genetics , COVID-19/diagnosis , COVID-19/virology , Gene Frequency , HIV Infections/diagnosis , HIV Infections/virology , HIV-1/genetics , Humans , Mutation , Polymorphism, Single Nucleotide , RNA Virus Infections/virology , Reproducibility of Results , SARS-CoV-2/genetics , Sensitivity and Specificity
20.
PLoS One ; 16(12): e0260820, 2021.
Article in English | MEDLINE | ID: covidwho-1581771

ABSTRACT

INTRODUCTION: The COVID-19 pandemic has caused widespread disruptions including to health services. In the early response to the pandemic many countries restricted population movements and some health services were suspended or limited. In late 2020 and early 2021 some countries re-imposed restrictions. Health authorities need to balance the potential harms of additional SARS-CoV-2 transmission due to contacts associated with health services against the benefits of those services, including fewer new HIV infections and deaths. This paper examines these trade-offs for select HIV services. METHODS: We used four HIV simulation models (Goals, HIV Synthesis, Optima HIV and EMOD) to estimate the benefits of continuing HIV services in terms of fewer new HIV infections and deaths. We used three COVID-19 transmission models (Covasim, Cooper/Smith and a simple contact model) to estimate the additional deaths due to SARS-CoV-2 transmission among health workers and clients. We examined four HIV services: voluntary medical male circumcision, HIV diagnostic testing, viral load testing and programs to prevent mother-to-child transmission. We compared COVID-19 deaths in 2020 and 2021 with HIV deaths occurring now and over the next 50 years discounted to present value. The models were applied to countries with a range of HIV and COVID-19 epidemics. RESULTS: Maintaining these HIV services could lead to additional COVID-19 deaths of 0.002 to 0.15 per 10,000 clients. HIV-related deaths averted are estimated to be much larger, 19-146 discounted deaths per 10,000 clients. DISCUSSION: While there is some additional short-term risk of SARS-CoV-2 transmission associated with providing HIV services, the risk of additional COVID-19 deaths is at least 100 times less than the HIV deaths averted by those services. Ministries of Health need to take into account many factors in deciding when and how to offer essential health services during the COVID-19 pandemic. This work shows that the benefits of continuing key HIV services are far larger than the risks of additional SARS-CoV-2 transmission.


Subject(s)
COVID-19/transmission , Health Services Accessibility/trends , Health Services/trends , COVID-19/complications , COVID-19/epidemiology , HIV Infections/complications , HIV Infections/epidemiology , HIV Infections/therapy , HIV-1/pathogenicity , Health Services Administration , Humans , Models, Theoretical , Pandemics/prevention & control , Risk Assessment/methods , SARS-CoV-2/pathogenicity
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