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1.
Top Antivir Med ; 29(3): 355-360, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34370417

RESUMO

The Conference on Retroviruses and Opportunistic Infections (CROI) serves as one of the most highly visible platforms upon which researchers gather to share the most recent findings on HIV/AIDS and, recently, on SARS-CoV-2 research. Research presentations on the novel coronavirus SARS-CoV-2 have become an increasing fixture at the conference since it was first covered at last year's conference. Although CROI 2021 was virtual, the organizers coordinated a seamless platform for presentations and poster sessions that effectively engaged the audience. CROI 2021 had a strong showing in terms of basic science presentations on HIV-1 and on SARS-CoV-2. Highlights included new insights into some of the more elusive steps in the viral replication cycle as well as new findings on immune escape strategies employed by SARS-CoV-2. The new investigator workshop has become a valuable resource that can be used by early stage and established investigators alike to receive state-of-the-art updates on research areas that might be outside their immediate areas of research. The new investigator workshop featured engaging presentations on novel aspects of HIV-1 and SARS-CoV-2 replication, impact of host immunity on HIV-1 and SARS-CoV-2, and approaches to assessing viral reservoir dynamics and strategies for viral reservoir elimination.


Assuntos
Pesquisa Biomédica , Congressos como Assunto , HIV-1/imunologia , SARS-CoV-2/imunologia , HIV-1/fisiologia , Humanos , SARS-CoV-2/fisiologia , Latência Viral
3.
Nat Commun ; 12(1): 4817, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376662

RESUMO

Engineered ectodomain trimer immunogens based on BG505 envelope glycoprotein are widely utilized as components of HIV vaccine development platforms. In this study, we used rhesus macaques to evaluate the immunogenicity of several stabilized BG505 SOSIP constructs both as free trimers and presented on a nanoparticle. We applied a cryoEM-based method for high-resolution mapping of polyclonal antibody responses elicited in immunized animals (cryoEMPEM). Mutational analysis coupled with neutralization assays were used to probe the neutralization potential at each epitope. We demonstrate that cryoEMPEM data can be used for rapid, high-resolution analysis of polyclonal antibody responses without the need for monoclonal antibody isolation. This approach allowed to resolve structurally distinct classes of antibodies that bind overlapping sites. In addition to comprehensive mapping of commonly targeted neutralizing and non-neutralizing epitopes in BG505 SOSIP immunogens, our analysis revealed that epitopes comprising engineered stabilizing mutations and of partially occupied glycosylation sites can be immunogenic.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Formação de Anticorpos/imunologia , Anticorpos Anti-HIV/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/ultraestrutura , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/ultraestrutura , Microscopia Crioeletrônica/métodos , Epitopos/química , Epitopos/imunologia , Epitopos/metabolismo , Glicosilação , Anticorpos Anti-HIV/química , Anticorpos Anti-HIV/ultraestrutura , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , HIV-1/genética , HIV-1/imunologia , HIV-1/metabolismo , Humanos , Macaca mulatta , Modelos Moleculares , Conformação Proteica , Produtos do Gene env do Vírus da Imunodeficiência Humana/ultraestrutura
4.
Sci Adv ; 7(31)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34321200

RESUMO

Rationally designed protein subunit vaccines are being developed for a variety of viruses including influenza, RSV, SARS-CoV-2, and HIV. These vaccines are based on stabilized versions of the primary targets of neutralizing antibodies on the viral surface, namely, viral fusion glycoproteins. While these immunogens display the epitopes of potent neutralizing antibodies, they also present epitopes recognized by non-neutralizing or weakly neutralizing ("off-target") antibodies. Using our recently developed electron microscopy polyclonal epitope mapping approach, we have uncovered a phenomenon wherein off-target antibodies elicited by HIV trimer subunit vaccines cause the otherwise highly stabilized trimeric proteins to degrade into cognate protomers. Further, we show that these protomers expose an expanded suite of off-target epitopes, normally occluded inside the prefusion conformation of trimer, that subsequently elicit further off-target antibody responses. Our study provides critical insights for further improvement of HIV subunit trimer vaccines for future rounds of the iterative vaccine design process.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Anti-HIV/química , Infecções por HIV/imunologia , HIV-1/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Vacinas contra a AIDS/química , Animais , COVID-19/imunologia , Feminino , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Humanos , Macaca mulatta , Coelhos , SARS-CoV-2/química , SARS-CoV-2/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia
5.
Front Immunol ; 12: 666991, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276657

RESUMO

The HIV-1 viral inhibition assay (VIA) measures CD8 T cell-mediated inhibition of HIV replication in CD4 T cells and is increasingly used for clinical testing of HIV vaccines and immunotherapies. The VIA has multiple sources of variability arising from in vitro HIV infection and co-culture of two T cell populations. Here, we describe multiple modifications to a 7-day VIA protocol, the most impactful being the introduction of independent replicate cultures for both HIV infected-CD4 (HIV-CD4) and HIV-CD4:CD8 T cell cultures. Virus inhibition was quantified using a ratio of weighted averages of p24+ cells in replicate cultures and the corresponding 95% confidence interval. An Excel template is provided to facilitate calculations. Virus inhibition was higher in people living with HIV suppressed on antiretroviral therapy (n=14, mean: 40.0%, median: 43.8%, range: 8.2 to 73.3%; p < 0.0001, two-tailed, exact Mann-Whitney test) compared to HIV-seronegative donors (n = 21, mean: -13.7%, median: -14.4%, range: -49.9 to 20.9%) and was stable over time (n = 6, mean %COV 9.4%, range 0.9 to 17.3%). Cross-sectional data were used to define 8% inhibition as the threshold to confidently detect specific CD8 T cell activity and determine the minimum number of culture replicates and p24+ cells needed to have 90% statistical power to detect this threshold. Last, we note that, in HIV seronegative donors, the addition of CD8 T cells to HIV infected CD4 T cells consistently increased HIV replication, though the level of increase varied markedly between donors. This co-culture effect may contribute to the weak correlations observed between CD8 T cell VIA and other measures of HIV-specific CD8 T cell function.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Soropositividade para HIV/imunologia , HIV-1/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Replicação Viral/imunologia , Antivirais/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Células Cultivadas , Técnicas de Cocultura , Estudos Transversais , Proteína do Núcleo p24 do HIV/imunologia , Soropositividade para HIV/sangue , Soropositividade para HIV/tratamento farmacológico , Soropositividade para HIV/virologia , Humanos , Resultado do Tratamento
6.
Molecules ; 26(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199200

RESUMO

Glycan-targeting antibodies and pseudo-antibodies have been extensively studied for their stoichiometry, avidity, and their interactions with the rapidly modifying glycan shield of influenza A. Broadly neutralizing antiviral agents bind in the same order when they neutralize enveloped viruses regardless of the location of epitopes to the host receptor binding site. Herein, we investigated the binding of cyanovirin-N (CV-N) to surface-expressed glycoproteins such as those of human immunodeficiency virus (HIV) gp120, hemagglutinin (HA), and Ebola (GP)1,2 and compared their binding affinities with the binding response to the trimer-folded gp140 using surface plasmon resonance (SPR). Binding-site knockout variants of an engineered dimeric CV-N molecule (CVN2) revealed a binding affinity that correlated with the number of (high-) affinity binding sites. Binding curves were specific for the interaction with N-linked glycans upon binding with two low-affinity carbohydrate binding sites. This biologically active assembly of a domain-swapped CVN2, or monomeric CV-N, bound to HA with a maximum KD of 2.7 nM. All three envelope spike proteins were recognized at a nanomolar KD, whereas binding to HIV neutralizing 2G12 by targeting HA and Ebola GP1,2 was measured in the µM range and specific for the bivalent binding scheme in SPR. In conclusion, invariant structural protein patterns provide a substrate for affinity maturation in the membrane-anchored HA regions, as well as the glycan shield on the membrane-distal HA top part. They can also induce high-affinity binding in antiviral CV-N to HA at two sites, and CVN2 binding is achieved at low-affinity binding sites.


Assuntos
Proteínas de Bactérias/metabolismo , Ebolavirus/metabolismo , HIV-1/metabolismo , Orthomyxoviridae/metabolismo , Polissacarídeos/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas do Envelope Viral/metabolismo , Proteínas de Bactérias/farmacologia , Sítios de Ligação , Ebolavirus/imunologia , Ebolavirus/isolamento & purificação , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/imunologia , HIV-1/isolamento & purificação , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/metabolismo , Doença pelo Vírus Ebola/virologia , Humanos , Influenza Humana/imunologia , Influenza Humana/metabolismo , Influenza Humana/virologia , Orthomyxoviridae/imunologia , Orthomyxoviridae/isolamento & purificação , Polissacarídeos/imunologia , Ligação Proteica , Proteínas Recombinantes/isolamento & purificação , Proteínas do Envelope Viral/imunologia
7.
Adv Protein Chem Struct Biol ; 126: 123-149, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34090613

RESUMO

Acquired immunodeficiency syndrome (AIDS) has affected millions of people worldwide. The human immunodeficiency virus (HIV) which infects T cells by using CD4 as its main receptor. Currently different treatments are available against HIV infection which can improve life expectancy of the patient but still it remains incurable. CCR5, which is also required as a co-receptor by majority of HIV strains for entry into the target cells, is now being targeted for gene therapy to develop HIV resistance in patients. In this review, we discuss different strategies that are being adapted for CCR5-gene disruption in CD4+ T cells and in hematopoietic stem cells (HSCs) to generate a HIV-resistant immune system in infected individuals. If CCR5 gene that can shape HIV-resistant T cells, it will aim in new approaches in clinical trials. But these techniques have certain weaknesses and disadvantages, and will need to be paired with other strategies to form a full HIV remedy. There is also a need to establish methods to help deter HIV re-emergence following targeted CCR5 therapy. But ultimately, this brought us a better knowledge of the road to HIV treatment.


Assuntos
Síndrome de Imunodeficiência Adquirida , Linfócitos T CD4-Positivos/imunologia , Terapia Genética , HIV-1 , Células-Tronco Hematopoéticas/imunologia , Receptores CCR5 , Síndrome de Imunodeficiência Adquirida/genética , Síndrome de Imunodeficiência Adquirida/imunologia , Síndrome de Imunodeficiência Adquirida/terapia , HIV-1/genética , HIV-1/imunologia , Humanos , Receptores CCR5/genética , Receptores CCR5/imunologia
8.
Viruses ; 13(5)2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064894

RESUMO

The year 2021 marks the 40th anniversary since physicians recognized symptoms of the acquired immunodeficiency syndrome (AIDS), a disease that has since caused more than 30 million deaths worldwide. Despite the passing of four decades, there remains no licensed vaccine for the human immunodeficiency virus type 1 (HIV-1), the etiologic agent of AIDS. Despite the development of outstanding anti-retroviral drugs, there are currently more than one-half million deaths each year due to AIDS. Here, we revisit a conventional vaccine strategy used for protection against variable pathogens like HIV-1, which combines an array of diverse surface antigens. The strategy uses antibody recognition patterns to categorize viruses and their surface antigens into groups. Then a leader is assigned for each group and group leaders are formulated into vaccine cocktails. The group leaders are 'natural mosaics', because they share one or more epitope(s) with each of the other group members. We encourage the application of this conventional approach to HIV-1 vaccine design. We suggest that the partnering of an antibody-instructed envelope cocktail with new vaccine vectors will yield a successful vaccine in the HIV-1 field.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , Animais , Desenho de Fármacos , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/imunologia , Humanos
10.
Viruses ; 13(5)2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064525

RESUMO

Mucins and mucin-like molecules are highly glycosylated, high-molecular-weight cell surface proteins that possess a semi-rigid and highly extended extracellular domain. P-selectin glycoprotein ligand-1 (PSGL-1), a mucin-like glycoprotein, has recently been found to restrict HIV-1 infectivity through virion incorporation that sterically hinders virus particle attachment to target cells. Here, we report the identification of a family of antiviral cellular proteins, named the Surface-Hinged, Rigidly-Extended Killer (SHREK) family of virion inactivators (PSGL-1, CD43, TIM-1, CD34, PODXL1, PODXL2, CD164, MUC1, MUC4, and TMEM123) that share similar structural characteristics with PSGL-1. We demonstrate that SHREK proteins block HIV-1 infectivity by inhibiting virus particle attachment to target cells. In addition, we demonstrate that SHREK proteins are broad-spectrum host antiviral factors that block the infection of diverse viruses such as influenza A. Furthermore, we demonstrate that a subset of SHREKs also blocks the infectivity of a hybrid alphavirus-SARS-CoV-2 (Ha-CoV-2) pseudovirus. These results suggest that SHREK proteins may be a part of host innate immunity against enveloped viruses.


Assuntos
COVID-19/imunologia , Infecções por HIV/imunologia , Glicoproteínas de Membrana/metabolismo , Ligação Viral , Animais , COVID-19/virologia , Cães , Células HEK293 , HIV-1/imunologia , Células HeLa , Interações entre Hospedeiro e Microrganismos , Humanos , Imunidade Inata , Células Madin Darby de Rim Canino , Mucinas/farmacologia , SARS-CoV-2/imunologia
11.
BMC Infect Dis ; 21(1): 569, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34126953

RESUMO

BACKGROUND: NEW LAV BLOT I and II (LAV I and LAV II), they were only option for human immunodeficiency virus (HIV) confirmatory test, following HIV screening test using HIV Ag/Ab combination test in Japan. We evaluated the performance of Geenius HIV-1/2 Confirmatory Assay (Geenius), both as a confirmatory test and for differentiation between HIV-1 and HIV-2, in comparison with LAV I and LAV II. METHODS: Eighty-nine HIV-1-positive plasma specimens, one anti-HIV-1 low-titer performance panel, 10 seroconversion panels, and two anti-HIV-1/2 combo performance panels were tested. The results were read with the Geenius Reader and by visual reading. RESULTS: All 89 HIV-1-positive plasma specimens were identified as HIV-1-positive using Geenius; this 100% success rate was superior to that with LAV I (95.5% using WHO criteria, 98.9% using CDC criteria). The HIV-1-positive specimens showed low cross-reactivity with HIV-2 lines in Geenius. The sensitivity of Geenius for HIV-1 detection was the same as or greater than that of LAV I, but less than that of Genscreen HIV Ag-Ab ULT, in our analysis of the commercial performance and seroconversion panels. In contrast, five of the 13 HIV-2-positive specimens that had been identified as HIV-positive untypable by visual reading because of their cross-reactivity to HIV-1 lines were successfully identified by the Geenius Reader as HIV-2-positive with cross-reactivity. CONCLUSIONS: Geenius provides strong performance for HIV confirmatory tests and HIV-1 differentiation tests. However, when visual reading is used, its performance in HIV-2 differentiation is less reliable. Because HIV-2 infection has been sporadically reported in Japan, the use of the Geenius Reader is preferable to ensure more reliable HIV-1/HIV-2 differentiation.


Assuntos
Sorodiagnóstico da AIDS/métodos , Infecções por HIV/diagnóstico , HIV-1/isolamento & purificação , HIV-2/isolamento & purificação , Sorodiagnóstico da AIDS/instrumentação , Reações Cruzadas , Diagnóstico Diferencial , Anticorpos Anti-HIV/sangue , HIV-1/imunologia , HIV-2/imunologia , Humanos , Japão , Programas de Rastreamento , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
12.
J Virol ; 95(15): e0236820, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34011553

RESUMO

The development of efficient vaccine approaches against HIV infection remains challenging in the vaccine field. Here, we developed an Ebola virus envelope glycoprotein (EboGP)-based chimeric fusion protein system and demonstrated that replacement of the mucin-like domain (MLD) of EboGP with HIV C2-V3-C3 (134 amino acids [aa]) or C2-V3-C3-V4-C4-V5-C5 (243 aa) polypeptides (EbGPΔM-V3 and EbGPΔM-V3-V5, respectively) still maintained the efficiency of EboGP-mediated viral entry into human macrophages and dendritic cells (DCs). Animal studies using mice revealed that immunization with virus-like particles (VLPs) containing the above chimeric proteins, especially EbGPΔM-V3, induced significantly more potent anti-HIV antibodies than HIV gp120 alone in mouse serum and vaginal fluid. Moreover, the splenocytes isolated from mice immunized with VLPs containing EbGPΔM-V3 produced significantly higher levels of gamma interferon (IFN-γ), interleukin 2 (IL-2), IL-4, IL-5, and macrophage inflammatory protein 1α (MIP-1α). Additionally, we demonstrated that coexpression of EbGPΔM-V3 and the HIV Env glycoprotein in a recombinant vesicular stomatitis virus (rVSV) vector elicited robust anti-HIV antibodies that may have specifically recognized epitopes outside or inside the C2-V3-C3 region of HIV-1 gp120 and cross-reacted with the gp120 from different HIV strains. Thus, this study has demonstrated the great potential of this DC-targeting vaccine platform as a new vaccine approach for improving immunogen delivery and increasing vaccine efficacy. IMPORTANCE Currently, there are more than 38.5 million reported cases of HIV globally. To date, there is no approved vaccine for HIV-1 infection. Thus, the development of an effective vaccine against HIV infection remains a global priority. This study revealed the efficacy of a novel dendritic cell (DC)-targeting vaccination approach against HIV-1. The results clearly show that the immunization of mice with virus-like particles (VLPs) and VSVs containing HIV Env and a fusion protein composed of a DC-targeting domain of Ebola virus GP with HIV C2-V3-C3 polypeptides (EbGPΔM-V3) could induce robust immune responses against HIV-1 Env and/or Gag in serum and vaginal mucosa. These findings provide a proof of concept of this novel and efficient DC-targeting vaccine approach in delivering various antigenic polypeptides of HIV-1 and/or other emergent infections to the host antigen-presenting cells to prevent HIV and other viral infections.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Células Dendríticas/imunologia , HIV-1/imunologia , Proteínas do Envelope Viral/imunologia , Animais , Linhagem Celular Tumoral , Quimiocina CCL3/imunologia , Chlorocebus aethiops , Ebolavirus/imunologia , Feminino , Células HEK293 , Infecções por HIV/prevenção & controle , Humanos , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Células THP-1 , Vacinas de Partículas Semelhantes a Vírus/imunologia , Células Vero , Vírus da Estomatite Vesicular Indiana/genética
13.
Lancet HIV ; 8(7): e449-e452, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34029515

RESUMO

The advanced-phase HIV prevention vaccine trials done in South Africa (HVTN 702) and in Thailand (RV144), which both investigated canarypox vectors and adjuvanted gp120 proteins, gave rise to different results. The South African trial did not find vaccine efficacy, whereas the Thai trial had modest, but statistically significant, success with the modified intention-to-treat analysis prespecified in the protocols of both studies. An understanding of the differences between the studies is required to avoid the possible, but erroneous, conclusion that the results from the South African trial negatively affect the results of the Thai trial.


Assuntos
Vacinas contra a AIDS/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Vacinas contra a AIDS/administração & dosagem , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , África do Sul , Tailândia
14.
Cell ; 184(11): 2955-2972.e25, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34019795

RESUMO

Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.


Assuntos
Anticorpos Neutralizantes/imunologia , HIV-1/imunologia , Fragmentos Fab das Imunoglobulinas/imunologia , Polissacarídeos/imunologia , SARS-CoV-2/imunologia , Vírus da Imunodeficiência Símia/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Animais , Linfócitos B/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , COVID-19/imunologia , Dimerização , Epitopos/imunologia , Glicosilação , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Humanos , Fragmentos Fab das Imunoglobulinas/química , Macaca mulatta , Polissacarídeos/química , Receptores de Antígenos de Linfócitos B/química , Vírus da Imunodeficiência Símia/genética , Vacinas/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética
15.
Lancet HIV ; 8(6): e334-e341, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33933189

RESUMO

BACKGROUND: Most cohorts show similar or lower COVID-19 incidence among people living with HIV compared with the general population. However, incidence might be affected by lower testing rates among vulnerable populations. We aimed to compare SARS-CoV-2 IgG seroprevalence, disease severity, and neutralising antibody activity after infection among people with and without HIV receiving care in a county hospital system over a 3-month period. METHODS: In this matched case-control observational study, remnant serum samples were collected between Aug 1 and Oct 31, 2020, from all people living with HIV who underwent routine outpatient laboratory testing in a municipal health-care system (San Francisco General Hospital, CA, USA). Samples from people living with HIV were date of collection-matched (same day) and age-matched (±5 years) to samples from randomly selected adults (aged 18 years or older) without HIV receiving care for chronic conditions at the same hospital. We compared seroprevalence by HIV status via mixed-effects logistic regression models, accounting for the matched structure of the data (random effects for the matched group), adjusting for age, sex, race or ethnicity, and clinical factors (ie, history of cardiovascular or pulmonary disease, and type 2 diabetes). Severe COVID-19 was assessed in participants with past SARS-CoV-2 (IgG or PCR) infection by chart review and compared with multivariable mixed-effects logistic regression, adjusting for age and sex. SARS-CoV-2 IgG, neutralising antibody titres, and antibody avidity were measured in serum of participants with previous positive PCR tests and compared with multivariable mixed-effects models, adjusting for age, sex, and time since PCR-confirmed SARS-CoV-2 infection. FINDINGS: 1138 samples from 955 people living with HIV and 1118 samples from 1062 people without HIV were tested. SARS-CoV-2 IgG seroprevalence was 3·7% (95% CI 2·4 to 5·0) among people with HIV compared with 7·4% (5·7 to 9·2) among people without HIV (adjusted odds ratio 0·50, 95% CI 0·30 to 0·83). Among 31 people with HIV and 70 people without HIV who had evidence of past infection, the odds of severe COVID-19 were 5·52 (95% CI 1·01 to 64·48) times higher among people living with HIV. Adjusting for time since PCR-confirmed infection, SARS-CoV-2 IgG concentrations were lower (percentage change -53%, 95% CI -4 to -76), pseudovirus neutralising antibody titres were lower (-67%, -25 to -86), and avidity was similar (7%, -73 to 87) among people living with HIV compared with those without HIV. INTERPRETATION: Although fewer infections were detected by SARS-CoV-2 IgG testing among people living with HIV than among those without HIV, people with HIV had more cases of severe COVID-19. Among people living with HIV with past SARS-CoV-2 infection, lower IgG concentrations and pseudovirus neutralising antibody titres might reflect a diminished serological response to infection, and the similar avidity could be driven by similar time since infection. FUNDING: US National Institute of Allergy and Infectious Diseases, US National Institutes of Health.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/imunologia , Infecções por HIV/imunologia , Imunoglobulina G/sangue , SARS-CoV-2/imunologia , Idoso , COVID-19/sangue , COVID-19/epidemiologia , COVID-19/virologia , Estudos de Casos e Controles , Feminino , Infecções por HIV/sangue , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/imunologia , HIV-1/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , SARS-CoV-2/patogenicidade , São Francisco/epidemiologia , Estudos Soroepidemiológicos , Índice de Gravidade de Doença
16.
J Clin Invest ; 131(12)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33945513

RESUMO

T cells are involved in control of coronavirus disease 2019 (COVID-19), but limited knowledge is available on the relationship between antigen-specific T cell response and disease severity. Here, we used flow cytometry to assess the magnitude, function, and phenotype of SARS coronavirus 2-specific (SARS-CoV-2-specific) CD4+ T cells in 95 hospitalized COVID-19 patients, 38 of them being HIV-1 and/or tuberculosis (TB) coinfected, and 38 non-COVID-19 patients. We showed that SARS-CoV-2-specific CD4+ T cell attributes, rather than magnitude, were associated with disease severity, with severe disease being characterized by poor polyfunctional potential, reduced proliferation capacity, and enhanced HLA-DR expression. Moreover, HIV-1 and TB coinfection skewed the SARS-CoV-2 T cell response. HIV-1-mediated CD4+ T cell depletion associated with suboptimal T cell and humoral immune responses to SARS-CoV-2, and a decrease in the polyfunctional capacity of SARS-CoV-2-specific CD4+ T cells was observed in COVID-19 patients with active TB. Our results also revealed that COVID-19 patients displayed reduced frequency of Mycobacterium tuberculosis-specific CD4+ T cells, with possible implications for TB disease progression. These results corroborate the important role of SARS-CoV-2-specific T cells in COVID-19 pathogenesis and support the concept of altered T cell functions in patients with severe disease.


Assuntos
Linfócitos T CD4-Positivos/imunologia , COVID-19/imunologia , Coinfecção/imunologia , HIV-1/imunologia , Mycobacterium tuberculosis/imunologia , SARS-CoV-2/imunologia , Tuberculose/imunologia , Adulto , Idoso , Linfócitos T CD4-Positivos/patologia , COVID-19/patologia , Coinfecção/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Tuberculose/patologia
17.
J Virol ; 95(15): e0231120, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980591

RESUMO

Type I interferons (IFNs) are a family of cytokines that represent a first line of defense against virus infections. The 12 different IFN-α subtypes share a receptor on target cells and trigger similar signaling cascades. Several studies have collectively shown that this apparent redundancy conceals qualitatively different responses induced by individual subtypes, which display different efficacies of inhibition of HIV replication. Some studies, however, provided evidence that the disparities are quantitative rather than qualitative. Since RNA expression analyses show a large but incomplete overlap of the genes induced, they may support both models. To explore if the IFN-α subtypes induce functionally relevant different anti-HIV activities, we have compared the efficacies of inhibition of all 12 subtypes on HIV spread and on specific steps of the viral replication cycle, including viral entry, reverse transcription, protein synthesis, and virus release. Finding different hierarchies of inhibition would validate the induction of qualitatively different responses. We found that while most subtypes similarly inhibit virus entry, they display distinctive potencies on other early steps of HIV replication. In addition, only some subtypes were able to target effectively the late steps. The extent of induction of known anti-HIV factors helps to explain some, but not all differences observed, confirming the participation of additional IFN-induced anti-HIV effectors. Our findings support the notion that different IFN-α subtypes can induce the expression of qualitatively different antiviral activities. IMPORTANCE The initial response against viruses relies in large part on type I interferons, which include 12 subtypes of IFN-α. These cytokines bind to a common receptor on the cell surface and trigger the expression of incompletely overlapping sets of genes. Whether the anti-HIV responses induced by IFN-α subtypes differ in the extent of expression or in the nature of the genes involved remains debated. Also, RNA expression profiles led to opposite conclusions, depending on the importance attributed to the induction of common or distinctive genes. To explore if relevant anti-HIV activities can be differently induced by the IFN-α subtypes, we compared their relative efficacies on specific steps of the replication cycle. We show that the hierarchy of IFN potencies depends on the step analyzed, supporting qualitatively different responses. This work will also prompt the search for novel IFN-induced anti-HIV factors acting on specific steps of the replication cycle.


Assuntos
HIV-1/crescimento & desenvolvimento , Interferon-alfa/classificação , Interferon-alfa/imunologia , Receptor de Interferon alfa e beta/metabolismo , Replicação Viral/fisiologia , Linhagem Celular , Células HEK293 , HIV-1/imunologia , Humanos , Imunidade Inata/imunologia , Transdução de Sinais/imunologia , Internalização do Vírus
18.
J Virol ; 95(15): e0235020, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980592

RESUMO

HIV-1 infection is initiated by the viral glycoprotein Env, which, after interaction with cellular coreceptors, adopts a transient conformation known as the prehairpin intermediate (PHI). The N-heptad repeat (NHR) is a highly conserved region of gp41 exposed in the PHI; it is the target of the FDA-approved drug enfuvirtide and of neutralizing monoclonal antibodies (mAbs). However, to date, these mAbs have only been weakly effective against tier-1 HIV-1 strains, which are most sensitive to neutralizing antibodies. Here, we engineered and tested 11 IgG variants of D5, an anti-NHR mAb, by recombining previously described mutations in four of D5's six antibody complementarity-determining regions. One variant, D5_AR, demonstrated 6-fold enhancement in the 50% inhibitory dose (ID50) against lentivirus pseudotyped with HXB2 Env. D5_AR exhibited weak cross-clade neutralizing activity against a diverse set of tier-2 HIV-1 viruses, which are less sensitive to neutralizing antibodies than tier-1 viruses and are the target of current antibody-based vaccine efforts. In addition, the neutralization potency of D5_AR IgG was greatly enhanced in target cells expressing FcγRI, with ID50 values of <0.1 µg/ml; this immunoglobulin receptor is expressed on macrophages and dendritic cells, which are implicated in the early stages of HIV-1 infection of mucosal surfaces. D5 and D5_AR have equivalent neutralization potency in IgG, Fab, and single-chain variable-fragment (scFv) formats, indicating that neutralization is not impacted by steric hindrance. Taken together, these results provide support for vaccine strategies that target the PHI by eliciting antibodies against the gp41 NHR and support investigation of anti-NHR mAbs in nonhuman primate passive immunization studies. IMPORTANCE Despite advances in antiretroviral therapy, HIV remains a global epidemic and has claimed more than 32 million lives. Accordingly, developing an effective HIV vaccine remains an urgent public health need. The gp41 N-heptad repeat (NHR) of the HIV-1 prehairpin intermediate (PHI) is highly conserved (>90%) and is inhibited by the FDA-approved drug enfuvirtide, making it an attractive vaccine target. However, to date, anti-NHR antibodies have not been potent. Here, we engineered D5_AR, a more potent variant of the anti-NHR antibody D5, and established its ability to inhibit HIV-1 strains that are more difficult to neutralize and are more representative of circulating strains (tier-2 strains). The neutralizing activity of D5_AR was greatly potentiated in cells expressing FcγRI; FcγRI is expressed on cells that are implicated at the earliest stages of sexual HIV-1 transmission. Taken together, these results bolster efforts to target the gp41 NHR and the PHI for vaccine development.


Assuntos
Fármacos Anti-HIV/farmacologia , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Proteína gp41 do Envelope de HIV/antagonistas & inibidores , HIV-1/imunologia , Anticorpos Monoclonais/imunologia , Linhagem Celular , Enfuvirtida/farmacologia , Células HEK293 , Proteína gp41 do Envelope de HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Humanos , Domínios Proteicos/imunologia
19.
AIDS Res Ther ; 18(1): 28, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952300

RESUMO

Coronavirus disease 2019 (COVID-19) was first detected in December 2019. In March 2020, the World Health Organization declared COVID-19 a pandemic. People with underlying medical conditions may be at greater risk of infection and experience complications from COVID-19. COVID-19 has the potential to affect People living with HIV (PLWH) in various ways, including be increased risk of COVID-19 acquisition and interruptions of HIV treatment and care. The purpose of this review article is to evaluate the impact of COVID-19 among PLWH. The contents focus on 4 topics: (1) the pathophysiology and host immune response of people infected with both SARS-CoV-2 and HIV, (2) present the clinical manifestations and treatment outcomes of persons with co-infection, (3) assess the impact of antiretroviral HIV drugs among PLWH infected with COVID-19 and (4) evaluate the impact of the COVID-19 pandemic on HIV services.


Assuntos
Antirretrovirais/uso terapêutico , COVID-19/patologia , Coinfecção/patologia , Infecções por HIV/patologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Adulto , COVID-19/complicações , COVID-19/tratamento farmacológico , COVID-19/imunologia , Coinfecção/imunologia , Citocinas/sangue , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , Hospedeiro Imunocomprometido/imunologia , Hospedeiro Imunocomprometido/fisiologia , Linfopenia/patologia , Pessoa de Meia-Idade , Resultado do Tratamento
20.
J Virol ; 95(13): e0021921, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-33853957

RESUMO

No prophylactic vaccine has provided robust protection against human immunodeficiency virus type 1 (HIV-1). Vaccine-induced broadly neutralizing antibodies (bNAbs) have not been achieved in humans and most animals; however, cows vaccinated with HIV-1 envelope trimers produce bNAbs with unusually long third heavy complementarity-determining regions (CDRH3s). Alongside neutralization, Fc-mediated effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADP), may be critical for in vivo bNAb antiviral activity. Here, we aimed to augment the Fc-dependent effector functions of a chimeric human-bovine bNAb, NC-Cow1, which binds the CD4 binding site (CD4bs) and exhibits broader and more potent neutralization than most human CD4bs bNAbs by using an exceptionally long 60-amino acid (aa) CDRH3. The bovine variable region of NC-Cow1 was paired with a human IgG1 Fc region mutated to create the following three variants: G236R/L328R (GRLR) that abrogates Fc-gamma receptor (FcγR) binding, and two variants that enhance binding, namely, G236A/S239D/I332E (GASDIE) and G236A/S239D/A330L/I332E (GASDALIE). Both GASDIE and GASDALIE improved binding to human FcγRIIA and FcγRIIIA, enhanced human natural killer (NK) cell activation, and mediated higher levels of ADCC and ADP activity than the wild-type human IgG1 Fc. GASDALIE mediated higher phagocytic activity than GASDIE. As expected, GRLR eliminated binding to FcγRs and did not mediate ADCC or ADP. We demonstrated that mutations in the human Fc region of bovine chimeric antibodies with ultralong CDRH3s could enhance antibody effector functions while maintaining envelope binding and neutralization. This study will have significant implications in the development of multifunctional anti-HIV antibodies, which may be important to prevent HIV-1 transmission in an antibody-based topical microbicide. IMPORTANCE Despite successful antiviral chemotherapy, human immunodeficiency virus (HIV) is still a lifelong persistent virus, and no vaccine yet prevents HIV transmission. Topical microbicides offer an important alternative method to prevent sexual transmission of HIV-1. With the production of highly potent anti-HIV-1 broadly neutralizing antibodies (bNAbs) and multifunctional antibodies, monoclonal antibodies are now important prophylactic agents. Recently discovered anti-HIV-1 bovine bNAbs (with higher potency and breadth than most human bNAbs) could be novel candidates as potent topical microbicides. Our study is significant as it demonstrates the compatibility of combining bovine-derived neutralization with human-derived antibody-effector functions. This study is a new approach to antibody engineering that strengthens the feasibility of using high-potency bovine variable region bNAbs with augmented Fc function and promotes them as a strong candidate for antibody-mediated therapies.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/prevenção & controle , Proteínas Recombinantes de Fusão/imunologia , Animais , Bovinos , Linhagem Celular , Infecções por HIV/transmissão , HIV-1/imunologia , Humanos , Imunoglobulina G/imunologia , Células Matadoras Naturais/imunologia , Fagocitose/imunologia , Engenharia de Proteínas , Receptores de IgG/imunologia
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