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1.
Cell ; 184(9): 2372-2383.e9, 2021 04 29.
Artículo en Inglés | MEDLINE | ID: mdl-33743213

RESUMEN

Vaccination elicits immune responses capable of potently neutralizing SARS-CoV-2. However, ongoing surveillance has revealed the emergence of variants harboring mutations in spike, the main target of neutralizing antibodies. To understand the impact of these variants, we evaluated the neutralization potency of 99 individuals that received one or two doses of either BNT162b2 or mRNA-1273 vaccines against pseudoviruses representing 10 globally circulating strains of SARS-CoV-2. Five of the 10 pseudoviruses, harboring receptor-binding domain mutations, including K417N/T, E484K, and N501Y, were highly resistant to neutralization. Cross-neutralization of B.1.351 variants was comparable to SARS-CoV and bat-derived WIV1-CoV, suggesting that a relatively small number of mutations can mediate potent escape from vaccine responses. While the clinical impact of neutralization resistance remains uncertain, these results highlight the potential for variants to escape from neutralizing humoral immunity and emphasize the need to develop broadly protective interventions against the evolving pandemic.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Vacunas contra la COVID-19/inmunología , Inmunidad Humoral , SARS-CoV-2/inmunología , Vacuna BNT162 , COVID-19/sangre , COVID-19/inmunología , COVID-19/virología , Células HEK293 , Humanos , Mutación/genética , Curva ROC , SARS-CoV-2/genética
3.
Nature ; 602(7898): 654-656, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35016196

RESUMEN

The emergence of the SARS-CoV-2 variant of concern Omicron (Pango lineage B.1.1.529), first identified in Botswana and South Africa, may compromise vaccine effectiveness and lead to re-infections1. Here we investigated Omicron escape from neutralization by antibodies from South African individuals vaccinated with Pfizer BNT162b2. We used blood samples taken soon after vaccination from individuals who were vaccinated and previously infected with SARS-CoV-2 or vaccinated with no evidence of previous infection. We isolated and sequence-confirmed live Omicron virus from an infected person and observed that Omicron requires the angiotensin-converting enzyme 2 (ACE2) receptor to infect cells. We compared plasma neutralization of Omicron relative to an ancestral SARS-CoV-2 strain and found that neutralization of ancestral virus was much higher in infected and vaccinated individuals compared with the vaccinated-only participants. However, both groups showed a 22-fold reduction in vaccine-elicited neutralization by the Omicron variant. Participants who were vaccinated and had previously been infected exhibited residual neutralization of Omicron similar to the level of neutralization of the ancestral virus observed in the vaccination-only group. These data support the notion that reasonable protection against Omicron may be maintained using vaccination approaches.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Vacuna BNT162/inmunología , Evasión Inmune/inmunología , Pruebas de Neutralización , SARS-CoV-2/inmunología , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Línea Celular , Chlorocebus aethiops , Humanos , Mutación , SARS-CoV-2/clasificación , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo
4.
Nature ; 607(7918): 356-359, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35523247

RESUMEN

The extent to which Omicron infection1-9, with or without previous vaccination, elicits protection against the previously dominant Delta (B.1.617.2) variant is unclear. Here we measured the neutralization capacity against variants of severe acute respiratory syndrome coronavirus 2 in 39 individuals in South Africa infected with the Omicron sublineage BA.1 starting at a median of 6 (interquartile range 3-9) days post symptom onset and continuing until last follow-up sample available, a median of 23 (interquartile range 19-27) days post symptoms to allow BA.1-elicited neutralizing immunity time to develop. Fifteen participants were vaccinated with Pfizer's BNT162b2 or Johnson & Johnson's Ad26.CoV2.S and had BA.1 breakthrough infections, and 24 were unvaccinated. BA.1 neutralization increased from a geometric mean 50% focus reduction neutralization test titre of 42 at enrolment to 575 at the last follow-up time point (13.6-fold) in vaccinated participants and from 46 to 272 (6.0-fold) in unvaccinated participants. Delta virus neutralization also increased, from 192 to 1,091 (5.7-fold) in vaccinated participants and from 28 to 91 (3.0-fold) in unvaccinated participants. At the last time point, unvaccinated individuals infected with BA.1 had low absolute levels of neutralization for the non-BA.1 viruses and 2.2-fold lower BA.1 neutralization, 12.0-fold lower Delta neutralization, 9.6-fold lower Beta variant neutralization, 17.9-fold lower ancestral virus neutralization and 4.8-fold lower Omicron sublineage BA.2 neutralization relative to vaccinated individuals infected with BA.1. These results indicate that hybrid immunity formed by vaccination and Omicron BA.1 infection should be protective against Delta and other variants. By contrast, infection with Omicron BA.1 alone offers limited cross-protection despite moderate enhancement.


Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Protección Cruzada , SARS-CoV-2 , Vacunación , Ad26COVS1/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Vacuna BNT162/inmunología , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/virología , Vacunas contra la COVID-19/inmunología , Protección Cruzada/inmunología , Humanos , SARS-CoV-2/clasificación , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Vacunación/estadística & datos numéricos
5.
Nature ; 603(7902): 706-714, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35104837

RESUMEN

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron's evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis.


Asunto(s)
COVID-19/patología , COVID-19/virología , Fusión de Membrana , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidad , Serina Endopeptidasas/metabolismo , Internalización del Virus , Adulto , Anciano , Anciano de 80 o más Años , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , Vacunas contra la COVID-19/inmunología , Línea Celular , Membrana Celular/metabolismo , Membrana Celular/virología , Chlorocebus aethiops , Convalecencia , Femenino , Humanos , Sueros Inmunes/inmunología , Intestinos/patología , Intestinos/virología , Pulmón/patología , Pulmón/virología , Masculino , Persona de Mediana Edad , Mutación , Mucosa Nasal/patología , Mucosa Nasal/virología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Técnicas de Cultivo de Tejidos , Virulencia , Replicación Viral
6.
Nature ; 603(7901): 488-492, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35102311

RESUMEN

The SARS-CoV-2 Omicron variant (B.1.1.529) has multiple spike protein mutations1,2 that contribute to viral escape from antibody neutralization3-6 and reduce vaccine protection from infection7,8. The extent to which other components of the adaptive response such as T cells may still target Omicron and contribute to protection from severe outcomes is unknown. Here we assessed the ability of T cells to react to Omicron spike protein in participants who were vaccinated with Ad26.CoV2.S or BNT162b2, or unvaccinated convalescent COVID-19 patients (n = 70). Between 70% and 80% of the CD4+ and CD8+ T cell response to spike was maintained across study groups. Moreover, the magnitude of Omicron cross-reactive T cells was similar for Beta (B.1.351) and Delta (B.1.617.2) variants, despite Omicron harbouring considerably more mutations. In patients who were hospitalized with Omicron infections (n = 19), there were comparable T cell responses to ancestral spike, nucleocapsid and membrane proteins to those in patients hospitalized in previous waves dominated by the ancestral, Beta or Delta variants (n = 49). Thus, despite extensive mutations and reduced susceptibility to neutralizing antibodies of Omicron, the majority of T cell responses induced by vaccination or infection cross-recognize the variant. It remains to be determined whether well-preserved T cell immunity to Omicron contributes to protection from severe COVID-19 and is linked to early clinical observations from South Africa and elsewhere9-12.


Asunto(s)
COVID-19/inmunología , COVID-19/virología , Reacciones Cruzadas/inmunología , Inmunidad Celular , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Linfocitos T/inmunología , Adulto , Anciano , Vacunas contra la COVID-19/inmunología , Convalecencia , Hospitalización , Humanos , Persona de Mediana Edad , SARS-CoV-2/química , SARS-CoV-2/clasificación
7.
Nature ; 593(7857): 142-146, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33780970

RESUMEN

SARS-CoV-2 variants of concern (VOC) have arisen independently at multiple locations1,2 and may reduce the efficacy of current vaccines that target the spike glycoprotein of SARS-CoV-23. Here, using a live-virus neutralization assay, we compared the neutralization of a non-VOC variant with the 501Y.V2 VOC (also known as B.1.351) using plasma collected from adults who were hospitalized with COVID-19 during the two waves of infection in South Africa, the second wave of which was dominated by infections with the 501Y.V2 variant. Sequencing demonstrated that infections of plasma donors from the first wave were with viruses that did not contain the mutations associated with 501Y.V2, except for one infection that contained the E484K substitution in the receptor-binding domain. The 501Y.V2 virus variant was effectively neutralized by plasma from individuals who were infected during the second wave. The first-wave virus variant was effectively neutralized by plasma from first-wave infections. However, the 501Y.V2 variant was poorly cross-neutralized by plasma from individuals with first-wave infections; the efficacy was reduced by 15.1-fold relative to neutralization of 501Y.V2 by plasma from individuals infected in the second wave. By contrast, cross-neutralization of first-wave virus variants using plasma from individuals with second-wave infections was more effective, showing only a 2.3-fold decrease relative to neutralization of first-wave virus variants by plasma from individuals infected in the first wave. Although we tested only one plasma sample from an individual infected with a SARS-CoV-2 variant with only the E484K substitution, this plasma sample potently neutralized both variants. The observed effective neutralization of first-wave virus by plasma from individuals infected with 501Y.V2 provides preliminary evidence that vaccines based on VOC sequences could retain activity against other circulating SARS-CoV-2 lineages.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , COVID-19/terapia , COVID-19/virología , Evasión Inmune/inmunología , Mutación , SARS-CoV-2/inmunología , Animales , Anticuerpos Neutralizantes/biosíntesis , Anticuerpos Antivirales/biosíntesis , COVID-19/epidemiología , Línea Celular , Chlorocebus aethiops , Humanos , Evasión Inmune/genética , Inmunización Pasiva , Pruebas de Neutralización , SARS-CoV-2/genética , Sudáfrica/epidemiología , Factores de Tiempo , Células Vero , Sueroterapia para COVID-19
8.
Nature ; 592(7854): 438-443, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33690265

RESUMEN

Continued uncontrolled transmission of SARS-CoV-2 in many parts of the world is creating conditions for substantial evolutionary changes to the virus1,2. Here we describe a newly arisen lineage of SARS-CoV-2 (designated 501Y.V2; also known as B.1.351 or 20H) that is defined by eight mutations in the spike protein, including three substitutions (K417N, E484K and N501Y) at residues in its receptor-binding domain that may have functional importance3-5. This lineage was identified in South Africa after the first wave of the epidemic in a severely affected metropolitan area (Nelson Mandela Bay) that is located on the coast of the Eastern Cape province. This lineage spread rapidly, and became dominant in Eastern Cape, Western Cape and KwaZulu-Natal provinces within weeks. Although the full import of the mutations is yet to be determined, the genomic data-which show rapid expansion and displacement of other lineages in several regions-suggest that this lineage is associated with a selection advantage that most plausibly results from increased transmissibility or immune escape6-8.


Asunto(s)
COVID-19/virología , Mutación , Filogenia , Filogeografía , SARS-CoV-2/genética , SARS-CoV-2/aislamiento & purificación , COVID-19/epidemiología , COVID-19/inmunología , COVID-19/transmisión , Análisis Mutacional de ADN , Evolución Molecular , Aptitud Genética , Humanos , Evasión Inmune , Modelos Moleculares , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Selección Genética , Sudáfrica/epidemiología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Factores de Tiempo
9.
Am J Respir Crit Care Med ; 209(7): 840-851, 2024 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-38226855

RESUMEN

Rationale: In the upper respiratory tract, replicating (culturable) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is recoverable for ∼4-8 days after symptom onset, but there is a paucity of data about the frequency and duration of replicating virus in the lower respiratory tract (i.e., the human lung).Objectives: We undertook lung tissue sampling (needle biopsy) shortly after death in 42 mechanically ventilated decedents during the Beta and Delta waves. An independent group of 18 ambulatory patients served as a control group.Methods: Lung biopsy cores from decedents underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling, and immunohistochemistry.Measurements and Main Results: Thirty-eight percent (16 of 42) of mechanically ventilated decedents had culturable virus in the lung for a median of 15 days (persisting for up to 4 wk) after symptom onset. Lung viral culture positivity was not associated with comorbidities or steroid use. Delta but not Beta variant lung culture positivity was associated with accelerated death and secondary bacterial infection (P < 0.05). Nasopharyngeal culture was negative in 23.1% (6 of 26) of decedents despite lung culture positivity. This hitherto undescribed biophenotype of lung-specific persisting viral replication was associated with an enhanced transcriptomic pulmonary proinflammatory response but with concurrent viral culture positivity.Conclusions: Concurrent rather than sequential active viral replication continues to drive a heightened proinflammatory response in the human lung beyond the second week of illness and was associated with variant-specific increased mortality and morbidity. These findings have potential implications for the design of interventional strategies and clinical management of patients with severe coronavirus disease (COVID-19).


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Pulmón , Prueba de COVID-19 , Replicación Viral
10.
N Engl J Med ; 384(20): 1885-1898, 2021 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-33725432

RESUMEN

BACKGROUND: Assessment of the safety and efficacy of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in different populations is essential, as is investigation of the efficacy of the vaccines against emerging SARS-CoV-2 variants of concern, including the B.1.351 (501Y.V2) variant first identified in South Africa. METHODS: We conducted a multicenter, double-blind, randomized, controlled trial to assess the safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) in people not infected with the human immunodeficiency virus (HIV) in South Africa. Participants 18 to less than 65 years of age were assigned in a 1:1 ratio to receive two doses of vaccine containing 5×1010 viral particles or placebo (0.9% sodium chloride solution) 21 to 35 days apart. Serum samples obtained from 25 participants after the second dose were tested by pseudovirus and live-virus neutralization assays against the original D614G virus and the B.1.351 variant. The primary end points were safety and efficacy of the vaccine against laboratory-confirmed symptomatic coronavirus 2019 illness (Covid-19) more than 14 days after the second dose. RESULTS: Between June 24 and November 9, 2020, we enrolled 2026 HIV-negative adults (median age, 30 years); 1010 and 1011 participants received at least one dose of placebo or vaccine, respectively. Both the pseudovirus and the live-virus neutralization assays showed greater resistance to the B.1.351 variant in serum samples obtained from vaccine recipients than in samples from placebo recipients. In the primary end-point analysis, mild-to-moderate Covid-19 developed in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9% (95% confidence interval [CI], -49.9 to 59.8). Among the 42 participants with Covid-19, 39 cases (95.1% of 41 with sequencing data) were caused by the B.1.351 variant; vaccine efficacy against this variant, analyzed as a secondary end point, was 10.4% (95% CI, -76.8 to 54.8). The incidence of serious adverse events was balanced between the vaccine and placebo groups. CONCLUSIONS: A two-dose regimen of the ChAdOx1 nCoV-19 vaccine did not show protection against mild-to-moderate Covid-19 due to the B.1.351 variant. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT04444674; Pan African Clinical Trials Registry number, PACTR202006922165132).


Asunto(s)
Anticuerpos Neutralizantes/sangre , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Inmunogenicidad Vacunal , SARS-CoV-2 , Adenoviridae , Adolescente , Adulto , Anticuerpos Neutralizantes/fisiología , COVID-19/epidemiología , COVID-19/inmunología , Prueba Serológica para COVID-19 , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/efectos adversos , ChAdOx1 nCoV-19 , Método Doble Ciego , Humanos , Persona de Mediana Edad , Sudáfrica , Linfocitos T/fisiología , Insuficiencia del Tratamiento , Potencia de la Vacuna , Adulto Joven
11.
PLoS Pathog ; 18(6): e1010592, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35767821

RESUMEN

Exposure histories to SARS-CoV-2 variants and vaccinations will shape the specificity of antibody responses. To understand the specificity of Delta-elicited antibody immunity, we characterize the polyclonal antibody response elicited by primary or mRNA vaccine-breakthrough Delta infections. Both types of infection elicit a neutralizing antibody response focused heavily on the receptor-binding domain (RBD). We use deep mutational scanning to show that mutations to the RBD's class 1 and class 2 epitopes, including sites 417, 478, and 484-486 often reduce binding of these Delta-elicited antibodies. The anti-Delta antibody response is more similar to that elicited by early 2020 viruses than the Beta variant, with mutations to the class 1 and 2, but not class 3 epitopes, having the largest effects on polyclonal antibody binding. In addition, mutations to the class 1 epitope (e.g., K417N) tend to have larger effects on antibody binding and neutralization in the Delta spike than in the D614G spike, both for vaccine- and Delta-infection-elicited antibodies. These results help elucidate how the antigenic impacts of SARS-CoV-2 mutations depend on exposure history.


Asunto(s)
COVID-19 , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Formación de Anticuerpos , Epítopos , Humanos , Pruebas de Neutralización , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Vacunas Sintéticas , Vacunas de ARNm
12.
PLoS Pathog ; 18(2): e1010248, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35134084

RESUMEN

Many SARS-CoV-2 variants have mutations at key sites targeted by antibodies. However, it is unknown if antibodies elicited by infection with these variants target the same or different regions of the viral spike as antibodies elicited by earlier viral isolates. Here we compare the specificities of polyclonal antibodies produced by humans infected with early 2020 isolates versus the B.1.351 variant of concern (also known as Beta or 20H/501Y.V2), which contains mutations in multiple key spike epitopes. The serum neutralizing activity of antibodies elicited by infection with both early 2020 viruses and B.1.351 is heavily focused on the spike receptor-binding domain (RBD). However, within the RBD, B.1.351-elicited antibodies are more focused on the "class 3" epitope spanning sites 443 to 452, and neutralization by these antibodies is notably less affected by mutations at residue 484. Our results show that SARS-CoV-2 variants can elicit polyclonal antibodies with different immunodominance hierarchies.


Asunto(s)
Anticuerpos Antivirales/inmunología , Formación de Anticuerpos/inmunología , COVID-19/inmunología , SARS-CoV-2/inmunología , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Anticuerpos Neutralizantes/inmunología , Epítopos/inmunología , Humanos , Inmunización Pasiva/métodos , Pruebas de Neutralización , SARS-CoV-2/genética , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Tratamiento Farmacológico de COVID-19
13.
J Infect Dis ; 227(2): 211-220, 2023 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-35975942

RESUMEN

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may be associated with worse clinical outcomes in people with human immunodeficiency virus (HIV) (PWH). We report anti-SARS-CoV-2 antibody responses in patients hospitalized with coronavirus disease 2019 in Durban, South Africa, during the second SARS-CoV-2 infection wave dominated by the Beta (B.1.351) variant. METHODS: Thirty-four participants with confirmed SARS-CoV-2 infection were followed up with weekly blood sampling to examine antibody levels and neutralization potency against SARS-CoV-2 variants. Participants included 18 PWH, of whom 11 were HIV viremic. RESULTS: SARS-CoV-2-specific antibody concentrations were generally lower in viremic PWH than in virologically suppressed PWH and HIV-negative participants, and neutralization of the Beta variant was 4.9-fold lower in viremic PWH. Most HIV-negative participants and antiretroviral therapy-suppressed PWH also neutralized the Delta (B.1.617.2) variant, whereas the majority of viremic PWH did not. CD4 cell counts <500/µL were associated with lower frequencies of immunoglobulin G and A seroconversion. In addition, there was a high correlation between a surrogate virus neutralization test and live virus neutralization against ancestral SARS-CoV-2 virus in both PWH and HIV-negative individuals, but correlation decreased for the Beta variant neutralization in PWH. CONCLUSIONS: HIV viremia was associated with reduced Beta variant neutralization. This highlights the importance of HIV suppression in maintaining an effective SARS-CoV-2 neutralization response.


Asunto(s)
COVID-19 , Infecciones por VIH , Humanos , SARS-CoV-2 , VIH , Viremia , Sudáfrica/epidemiología , Anticuerpos Antivirales , Infecciones por VIH/tratamiento farmacológico , Glicoproteína de la Espiga del Coronavirus , Anticuerpos Neutralizantes , Pruebas de Neutralización
14.
Mol Biol Evol ; 39(4)2022 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-35325204

RESUMEN

Among the 30 nonsynonymous nucleotide substitutions in the Omicron S-gene are 13 that have only rarely been seen in other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of the S-gene at sites that will likely impact (1) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (2) interactions of Spike with ACE2 receptors, and (3) the priming of Spike for membrane fusion. We show here that, based on both the rarity of these 13 mutations in intrapatient sequencing reads and patterns of selection at the codon sites where the mutations occur in SARS-CoV-2 and related sarbecoviruses, prior to the emergence of Omicron the mutations would have been predicted to decrease the fitness of any virus within which they occurred. We further propose that the mutations in each of the three clusters therefore cooperatively interact to both mitigate their individual fitness costs, and, in combination with other mutations, adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron overall previously known SARS-CoV-2 lineages, it is crucial to determine both how such complex and highly adaptive mutation constellations were assembled within the Omicron S-gene, and why, despite unprecedented global genomic surveillance efforts, the early stages of this assembly process went completely undetected.


Asunto(s)
COVID-19 , Glicoproteína de la Espiga del Coronavirus , COVID-19/genética , Humanos , Mutación , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genética
15.
PLoS Pathog ; 17(9): e1009871, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34555123

RESUMEN

HIV cerebrospinal fluid (CSF) escape, where HIV is suppressed in blood but detectable in CSF, occurs when HIV persists in the CNS despite antiretroviral therapy (ART). To determine the virus producing cell type and whether lowered CSF ART levels are responsible for CSF escape, we collected blood and CSF from 156 neurosymptomatic participants from Durban, South Africa. We observed that 28% of participants with an undetectable HIV blood viral load showed CSF escape. We detected host cell surface markers on the HIV envelope to determine the cellular source of HIV in participants on the first line regimen of efavirenz, emtricitabine, and tenofovir. We confirmed CD26 as a marker which could differentiate between T cells and macrophages and microglia, and quantified CD26 levels on the virion surface, comparing the result to virus from in vitro infected T cells or macrophages. The measured CD26 level was consistent with the presence of T cell produced virus. We found no significant differences in ART concentrations between CSF escape and fully suppressed individuals in CSF or blood, and did not observe a clear association with drug resistance mutations in CSF virus which would allow HIV to replicate. Hence, CSF HIV in the face of ART may at least partly originate in CD4+ T cell populations.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/líquido cefalorraquídeo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Linfocitos T/virología , Adulto , Alquinos/uso terapéutico , Benzoxazinas/uso terapéutico , Ciclopropanos/uso terapéutico , Emtricitabina/uso terapéutico , Femenino , VIH-1 , Humanos , Masculino , Persona de Mediana Edad , Tenofovir/uso terapéutico
17.
Clin Infect Dis ; 75(1): e249-e256, 2022 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-34472583

RESUMEN

BACKGROUND: There is limited understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis in African populations with a high burden of infectious disease comorbidities such as human immunodeficiency virus (HIV). The kinetics, magnitude, and duration of virus-specific antibodies and B-cell responses in people living with HIV (PLWH) in sub-Saharan Africa have not been fully characterized. METHODS: We longitudinally followed SARS-CoV-2-infected individuals in Durban, KwaZulu-Natal, South Africa, and characterized SARS-CoV-2 receptor-binding domain-specific immunoglobulin (Ig) M, IgG, and IgA weekly for 1 month and at 3 months post-diagnosis. Thirty of 72 (41.7%) were PLWH, 25/30 (83%) of whom were on antiretroviral therapy (ART) with full HIV suppression. Plasma neutralization was determined using a live virus neutralization assay, and antibody-secreting cell population frequencies were determined by flow cytometry. RESULTS: Similar seroconversion rates, time to peak antibody titer, peak magnitude, and durability of anti-SARS-CoV-2 IgM, IgG, and IgA were observed in people not living with HIV and PLWH with complete HIV suppression on ART. In addition, similar potency in a live virus neutralization assay was observed in both groups. Loss of IgA was significantly associated with age (P = .023) and a previous diagnosis of tuberculosis (P = .018). CONCLUSIONS: Similar antibody responses and neutralization potency in people not living with HIV and PLWH on stable ART in an African setting suggest that coronavirus disease 2019 (COVID-19) natural infections may confer comparable antibody immunity in these groups. This provides hope that COVID-19 vaccines will be effective in PLWH on stable ART.


Asunto(s)
COVID-19 , Infecciones por VIH , Anticuerpos Antivirales , Formación de Anticuerpos , Vacunas contra la COVID-19 , VIH , Infecciones por VIH/tratamiento farmacológico , Humanos , Inmunoglobulina A , Inmunoglobulina G , SARS-CoV-2 , Sudáfrica/epidemiología
18.
Clin Infect Dis ; 75(1): e857-e864, 2022 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-34893824

RESUMEN

BACKGROUND: People living with HIV (PLWH) have been reported to have a higher risk of more severe COVID-19 disease and death. We assessed the ability of the Ad26.CoV2.S vaccine to elicit neutralizing activity against the Delta variant in PLWH relative to HIV-negative individuals. We also examined effects of HIV status and suppression on Delta neutralization response in SARS-CoV-2-infected unvaccinated participants. METHODS: We enrolled participants who were vaccinated through the SISONKE South African clinical trial of the Ad26.CoV2.S vaccine in healthcare workers (HCWs). PLWH in this group had well-controlled HIV infection. We also enrolled unvaccinated participants previously infected with SARS-CoV-2. Neutralization capacity was assessed by a live virus neutralization assay of the Delta variant. RESULTS: Most Ad26.CoV2.S vaccinated HCWs were previously infected with SARS-CoV-2. In this group, Delta variant neutralization was 9-fold higher compared with the infected-only group and 26-fold higher relative to the vaccinated-only group. No decrease in Delta variant neutralization was observed in PLWH relative to HIV-negative participants. In contrast, SARS-CoV-2-infected, unvaccinated PLWH showed 7-fold lower neutralization and a higher frequency of nonresponders, with the highest frequency of nonresponders in people with HIV viremia. Vaccinated-only participants showed low neutralization capacity. CONCLUSIONS: The neutralization response of the Delta variant following Ad26.CoV2.S vaccination in PLWH with well-controlled HIV was not inferior to HIV-negative participants, irrespective of past SARS-CoV-2 infection. In SARS-CoV-2-infected and nonvaccinated participants, HIV infection reduced the neutralization response to SARS-CoV-2, with the strongest reduction in HIV viremic individuals.


Asunto(s)
Ad26COVS1 , COVID-19 , Infecciones por VIH , Ad26COVS1/administración & dosificación , Ad26COVS1/efectos adversos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , VIH , Infecciones por VIH/complicaciones , Humanos , SARS-CoV-2 , Vacunación
19.
PLoS Comput Biol ; 16(2): e1007482, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32017770

RESUMEN

HIV infection can be cleared with antiretroviral drugs if they are administered before exposure, where exposure occurs at low viral doses which infect one or few cells. However, infection clearance does not happen once infection is established, and this may be because of the very early formation of a reservoir of latently infected cells. Here we investigated whether initial low dose infection could be cleared with sub-optimal drug inhibition which allows ongoing viral replication, and hence does not require latency for viral persistence. We derived a model for infection clearance with inputs being drug effects on ongoing viral replication and initial number of infected cells. We experimentally tested the model by inhibiting low dose infection with the drug tenofovir, which interferes with initial infection, and atazanavir, which reduces the cellular virion burst size and hence inhibits replication only after initial infection. Drugs were used at concentrations which allowed infection to expand. Under these conditions, tenofovir dramatically increased clearance while atazanavir did not. Addition of latency to the model resulted in a minor decrease in clearance probability if the drug inhibited initial infection. If not, latency strongly decreased clearance even at low latent cell frequencies. Therefore, the ability of drugs to clear initial but not established infection can be recapitulated without latency and depends only on the ability to target initial infection. The presence of latency can dramatically decrease infection clearance, but only if the drug is unable to interfere with infection of the first cells.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Fármacos Anti-VIH/farmacología , Infecciones por VIH/patología , Humanos , Latencia del Virus , Replicación Viral/efectos de los fármacos
20.
PLoS Pathog ; 12(11): e1005964, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27812216

RESUMEN

Cell-to-cell spread of HIV, a directed mode of viral transmission, has been observed to be more rapid than cell-free infection. However, a mechanism for earlier onset of viral gene expression in cell-to-cell spread was previously uncharacterized. Here we used time-lapse microscopy combined with automated image analysis to quantify the timing of the onset of HIV gene expression in a fluorescent reporter cell line, as well as single cell staining for infection over time in primary cells. We compared cell-to-cell spread of HIV to cell-free infection, and limited both types of transmission to a two-hour window to minimize differences due to virus transit time to the cell. The mean time to detectable onset of viral gene expression in cell-to-cell spread was accelerated by 19% in the reporter cell line and by 35% in peripheral blood mononuclear cells relative to cell-free HIV infection. Neither factors secreted by infected cells, nor contact with infected cells in the absence of transmission, detectably changed onset. We recapitulated the earlier onset by infecting with multiple cell-free viruses per cell. Surprisingly, the acceleration in onset of viral gene expression was not explained by cooperativity between infecting virions. Instead, more rapid onset was consistent with a model where the fastest expressing virus out of the infecting virus pool sets the time for infection independently of the other co-infecting viruses.


Asunto(s)
Regulación Viral de la Expresión Génica/fisiología , Infecciones por VIH/genética , Infecciones por VIH/transmisión , Infecciones por VIH/virología , VIH-1/genética , Células Cultivadas , Citometría de Flujo , Humanos , Imagen de Lapso de Tiempo
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