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1.
Viruses ; 13(6)2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207152

RESUMO

This article reviews the current knowledge on how viruses may utilize Extracellular Vesicle Assisted Inflammatory Load (EVAIL) to exert pathologic activities. Viruses are classically considered to exert their pathologic actions through acute or chronic infection followed by the host response. This host response causes the release of cytokines leading to vascular endothelial cell dysfunction and cardiovascular complications. However, viruses may employ an alternative pathway to soluble cytokine-induced pathologies-by initiating the release of extracellular vesicles (EVs), including exosomes. The best-understood example of this alternative pathway is human immunodeficiency virus (HIV)-elicited EVs and their propensity to harm vascular endothelial cells. Specifically, an HIV-encoded accessory protein called the "negative factor" (Nef) was demonstrated in EVs from the body fluids of HIV patients on successful combined antiretroviral therapy (ART); it was also demonstrated to be sufficient in inducing endothelial and cardiovascular dysfunction. This review will highlight HIV-Nef as an example of how HIV can produce EVs loaded with proinflammatory cargo to disseminate cardiovascular pathologies. It will further discuss whether EV production can explain SARS-CoV-2-mediated pulmonary and cardiovascular pathologies.


Assuntos
Vesículas Extracelulares/imunologia , Vesículas Extracelulares/virologia , Inflamação/virologia , COVID-19/complicações , COVID-19/imunologia , COVID-19/fisiopatologia , Doenças Cardiovasculares/virologia , Células Endoteliais/patologia , Células Endoteliais/virologia , Exossomos/metabolismo , Infecções por HIV/complicações , Infecções por HIV/imunologia , Infecções por HIV/fisiopatologia , HIV-1/patogenicidade , Humanos , SARS-CoV-2/patogenicidade
2.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206330

RESUMO

The 'shock-and-kill' strategy to purge the latent HIV reservoir relies on latency-reversing agents (LRAs) to reactivate the provirus and subsequent immune-mediated killing of HIV-expressing cells. Yet, clinical trials employing histone deacetylase inhibitors (HDACis; Vorinostat, Romidepsin, Panobinostat) as LRAs failed to reduce the HIV reservoir size, stressing the need for more effective latency reversal strategies, such as 2-LRA combinations, and enhancement of the immune responses. Interestingly, several LRAs are employed to treat cancer because they up-modulate ligands for the NKG2D NK-cell activating receptor on tumor cells. Therefore, using in vitro T cell models of HIV latency and NK cells, we investigated the capacity of HDACis, either alone or combined with a distinct LRA, to potentiate the NKG2D/NKG2D ligands axis. While Bortezomib proteasome inhibitor was toxic for both T and NK cells, the GS-9620 TLR-7 agonist antagonized HIV reactivation and NKG2D ligand expression by HDACis. Conversely, co-administration of the Prostratin PKC agonist attenuated HDACi toxicity and, when combined with Romidepsin, stimulated HIV reactivation and further up-modulated NKG2D ligands on HIV+ T cells and NKG2D on NK cells, ultimately boosting NKG2D-mediated viral suppression by NK cells. These findings disclose limitations of LRA candidates and provide evidence that NK cell suppression of reactivated HIV may be modulated by specific 2-LRA combinations.


Assuntos
Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Inibidores de Histona Desacetilases/uso terapêutico , Células Matadoras Naturais/imunologia , Linfócitos T/virologia , Latência Viral , Infecções por HIV/imunologia , Infecções por HIV/fisiopatologia , Infecções por HIV/terapia , Humanos , Células Matadoras Naturais/fisiologia
3.
Viruses ; 13(7)2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209711

RESUMO

In stark contrast to the rapid development of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an effective human immunodeficiency virus (HIV) vaccine is still lacking. Furthermore, despite virologic suppression and CD4 T-cell count normalization with antiretroviral therapy (ART), people living with HIV (PLWH) still exhibit increased morbidity and mortality compared to the general population. Such differences in health outcomes are related to higher risk behaviors, but also to HIV-related immune activation and viral coinfections. Among these coinfections, cytomegalovirus (CMV) latent infection is a well-known inducer of long-term immune dysregulation. Cytomegalovirus contributes to the persistent immune activation in PLWH receiving ART by directly skewing immune response toward itself, and by increasing immune activation through modification of the gut microbiota and microbial translocation. In addition, through induction of immunosenescence, CMV has been associated with a decreased response to infections and vaccines. This review provides a comprehensive overview of the influence of CMV on the immune system, the mechanisms underlying a reduced response to vaccines, and discuss new therapeutic advances targeting CMV that could be used to improve vaccine response in PLWH.


Assuntos
Coinfecção/virologia , Infecções por Citomegalovirus/virologia , Citomegalovirus/imunologia , Infecções por HIV/virologia , Vacinas/imunologia , Animais , Fármacos Anti-HIV/uso terapêutico , Ensaios Clínicos como Assunto , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/imunologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/patologia , Trato Gastrointestinal/virologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Imunossenescência , Inflamação , Infecção Latente/imunologia , Infecção Latente/virologia , Camundongos , Vacinas/administração & dosagem
4.
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
6.
J Immunother Cancer ; 9(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34117116

RESUMO

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. COVID-19 has highly variable disease severity and a bimodal course characterized by acute respiratory viral infection followed by hyperinflammation in a subset of patients with severe disease. This immune dysregulation is characterized by lymphocytopenia, elevated levels of plasma cytokines and proliferative and exhausted T cells, among other dysfunctional cell types. Immunocompromised persons often fare worse in the context of acute respiratory infections, but preliminary data suggest this may not hold true for COVID-19. In this review, we explore the effect of SARS-CoV-2 infection on mortality in four populations with distinct forms of immunocompromise: (1) persons with hematological malignancies (HM) and hematopoietic stem cell transplant (HCT) recipients; (2) solid organ transplant recipients (SOTRs); (3) persons with rheumatological diseases; and (4) persons living with HIV (PLWH). For each population, key immunological defects are described and how these relate to the immune dysregulation in COVID-19. Next, outcomes including mortality after SARS-CoV-2 infection are described for each population, giving comparisons to the general population of age-matched and comorbidity-matched controls. In these four populations, iatrogenic or disease-related immunosuppression is not clearly associated with poor prognosis in HM, HCT, SOTR, rheumatological diseases, or HIV. However, certain individual immunosuppressants or disease states may be associated with harmful or beneficial effects, including harm from severe CD4 lymphocytopenia in PLWH and possible benefit to the calcineurin inhibitor ciclosporin in SOTRs, or tumor necrosis factor-α inhibitors in persons with rheumatic diseases. Lastly, insights gained from clinical and translational studies are explored as to the relevance for repurposing of immunosuppressive host-directed therapies for the treatment of hyperinflammation in COVID-19 in the general population.


Assuntos
COVID-19 , Reposicionamento de Medicamentos , Hospedeiro Imunocomprometido , Imunossupressores/uso terapêutico , Imunoterapia , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/terapia , Comorbidade , Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/estatística & dados numéricos , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Humanos , Hospedeiro Imunocomprometido/fisiologia , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Imunoterapia/estatística & dados numéricos , Mortalidade , Pandemias , Prognóstico , Doenças Reumáticas/epidemiologia , SARS-CoV-2/fisiologia , Transplantados/estatística & dados numéricos
7.
BMC Infect Dis ; 21(1): 613, 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34174839

RESUMO

BACKGROUND: Cytomegalovirus (CMV) retinitis is a common opportunistic infection in patients with acquired immunodeficiency syndrome. The common funduscopic manifestations are haemorrhagic necrotising variety and granular variety. Frosted branch angiitis (FBA), as a special form, when it occurred after antiretroviral therapy(ART), could possibly be associated with immune reconstitution. We report a case of FBA secondary to CMV infection-associated unmasking immune reconstitution inflammatory syndrome (IRIS). CASE PRESENTATION: A 27-year-old man with human immunodeficiency virus infection developed FBA after 35 days of ART. The left Aqueous humour (AqH) tested positive for CMV DNA, and the patient was diagnosed with CMV retinitis. The degree of intraocular inflammation was reflected by increased levels of interleukin (IL)-6 and IL-8 in AqH. After anti-CMV treatment and continuous ART for several months, his FBA and vision significantly improved. CMV DNA became undetectable in the left AqH, and the IL-6 and IL-8 levels in AqH decreased. CONCLUSION: FBA could be a sign of CMV-associated unmasking IRIS. Anti-CMV treatment alone or combination with steroid treatment may be administered, depending on the changes in CMV DNA load and immunologic profile of AqH.


Assuntos
Retinite por Citomegalovirus/complicações , Infecções por HIV/complicações , Síndrome Inflamatória da Reconstituição Imune/diagnóstico , Vasculite/diagnóstico , Síndrome de Imunodeficiência Adquirida/complicações , Adulto , Citomegalovirus/imunologia , Retinite por Citomegalovirus/diagnóstico , Retinite por Citomegalovirus/imunologia , Diagnóstico Diferencial , HIV , Infecções por HIV/diagnóstico , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Síndrome Inflamatória da Reconstituição Imune/complicações , Masculino , Vasculite/complicações , Vasculite/imunologia
8.
BMC Infect Dis ; 21(1): 592, 2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34157979

RESUMO

BACKGROUND: Factors predicting peripheral blood total HIV-1 DNA size in chronically infected patients with successfully suppressed viremia remain unclear. Prognostic power of such factors are of clinical significance for making clinical decisions. METHODS: Two sets of study populations were included: 490 China AIDS Clinical Trial (CACT) participants (Training cohort, followed up for 144 to 288 weeks) and 117 outpatients from Peking Union Medical College Hospital (PUMCH) (Validation cohort, followed up for more than 96 weeks). All patients were chronically HIV-1-infected and achieved successful HIV-1 plasma RNA suppression within week 48. Total HIV-1 DNA in blood at baseline, 12, 24, 48, 96, 144 and 288 weeks after combined antiretroviral therapy (cART) initiation were quantified. Generalized estimating equations and logistic regression methods were used to derive and validate a predictive model of total HIV-1 DNA after 96 weeks of cART. RESULTS: The total HIV-1 DNA rapidly decreased from baseline [median = 3.00 log10 copies/106 peripheral blood mononuclear cells (PBMCs)] to week 24 (median = 2.55 log10 copies/106 PBMCs), and leveled off afterwards. Of the 490 patients who had successful HIV-1 plasma RNA suppression by 96 w post-cART, 92 (18.8%) had a low total HIV-1 DNA count (< 100 copies/106 PBMCs) at week 96. In the predictive model, lower baseline total HIV-1 DNA [risk ratio (RR) = 0.08, per 1 log10 copies/106 PBMCs, P < 0.001] and higher baseline CD4+ T cell count (RR = 1.72, per 100 cells/µL, P < 0.001) were significantly associated with a low total HIV-1 DNA count at week 96. In an independent cohort of 117 patients, this model achieved a sensitivity of 75.00% and specificity of 69.52%. CONCLUSIONS: Baseline total HIV-1 DNA and CD4+ T cell count are two independent predictors of total HIV-1 DNA after treatment. The derived model based on these two baseline factors provides a useful prognostic tool in predicting HIV-1 DNA reservoir control during cART.


Assuntos
DNA Viral/sangue , HIV-1 , Leucócitos Mononucleares/virologia , Modelos Estatísticos , Carga Viral , Adulto , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , China/epidemiologia , Estudos de Coortes , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Estudos Longitudinais , Masculino , Sensibilidade e Especificidade , Viremia/tratamento farmacológico
9.
Medicine (Baltimore) ; 100(23): e25313, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34114978

RESUMO

ABSTRACT: Changes in tryptophan metabolism affect human physiology including the immune system, mood, and sleep and are associated with human immunodeficiency virus (HIV) pathogenesis. This study investigates whether the treatment of HIV-infected individuals with the neurokinin-1 receptor antagonist, aprepitant, alters tryptophan metabolism.This study utilized archival samples from 3 phase 1B clinical trials "Anti-HIV Neuroimmunomodulatory Therapy with Neurokinin-1 Antagonist Aprepitant"-2 double-blinded, placebo-controlled, and 1 open-label study. We tested samples from a total of 57 individuals: 26 combination antiretroviral therapy (cART) naïve individuals receiving aprepitant, 19 cART naïve individuals receiving placebo, and 12 individuals on a ritonavir-containing cART regimen receiving aprepitant. We evaluated the effect of aprepitant on tryptophan metabolism by measuring levels of kynurenine and tryptophan in archival plasma samples and calculating the kynurenine to tryptophan ratio.Aprepitant treatment affected tryptophan metabolism in both cART treated and cART naïve individuals with more profound effects in patients receiving cART. While aprepitant treatment affected tryptophan metabolism in all HIV-infected patients, it only significantly decreased kynurenine to tryptophan ratio in cART treated individuals. Aprepitant treatment offers an opportunity to target inflammation and mood disorders frequently co-existing in chronic HIV infection.


Assuntos
Aprepitanto , Infecções por HIV , Transtornos do Humor , Neuroimunomodulação/efeitos dos fármacos , Ritonavir , Triptofano/metabolismo , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Aprepitanto/administração & dosagem , Aprepitanto/efeitos adversos , Contagem de Linfócito CD4/métodos , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/psicologia , Infecções por HIV/virologia , Humanos , Cinurenina/análise , Masculino , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/etiologia , Antagonistas dos Receptores de Neurocinina-1/administração & dosagem , Antagonistas dos Receptores de Neurocinina-1/efeitos adversos , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Resultado do Tratamento
10.
BMC Infect Dis ; 21(1): 561, 2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34118891

RESUMO

BACKGROUND: People living with human immunodeficiency virus (HIV) with immuno-virological discordant responses are at an increased risk to develop acquired immunodeficiency syndrome (AIDS) and severe non AIDS events which are risk factors for death. This study was aimed to assess prevalence of immuno- virological discordant responses and associated risk factors among highly active antiretroviral therapy (HAART) users in Tigray, Northern Ethiopia. METHODS: A cross sectional study was conducted from September to December 30, 2016 on 260 people living with HIV who started first line HAART from January 2008 to March 2016 at Mekelle hospital and Ayder comprehensive specialized hospital. Baseline and follow-up clinical data and CD4+ result were collected from patient charts. Besides, socio-demographic data and blood samples for CD4 + count and viral load measurement were collected during data collection period. Fisher's exact test, bivariate and multivariate logistic regressions were used for data analysis. P-value < 0.05 with 95% CI was considered as statistically significant. RESULT: Among the 260 study participants, 8.80% (95% Confidence Interval (CI) =8.77-8.84%) and 2.70% (95% CI = 2.68-2.72%) had virological and immunological discordant responses, respectively with an overall immuno-virological discordance response of 11.50% (95% CI = 11.46-11.54%). The median age of the study participants at HAART initiation was 35 (IQR: 28-44 years). More than half (58.1%) of the study participants were females. Age at or below 35 years old at HAART initiation (AOR ((95% CI) = 4.25(1.48-12.23), p = 0.007)), male gender ((Adjusted Odds Ratio (AOR) (95% CI) =1.71(1.13-1.10), p = 0.029)), type of regimen given ((AOR(95% CI) = 0.30 (0.10-0.88), p = 0.028)) and good treatment adherence ((AOR (95% CI) = 0.12 (0.030-0.0.48), p = 0.003)) were associated risk factors for virological discordant response. Likewise, immunological discordant response was associated with tuberculosis co-infections (p = 0.016), hepatitis B virus co-infections (p = 0.05) and low CD4+ count (≤100 cells/µl) at baseline (p = 0.026). CONCLUSIONS: Over all, immuno-virological discordance response was 11.5% in the study area. Males, low baseline CD4+ count, poor/fair treatment adherence, and TB and HBV co-infections were significantly associated with higher immuno-virological discordance. We recommend that decision of patient treatment outcome, regimen change and patient management response should be done using trends of both viral load and CD4+ count concurrently.


Assuntos
Antirretrovirais , Infecções por HIV , HIV , Adulto , Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Estudos Transversais , Etiópia/epidemiologia , Feminino , HIV/efeitos dos fármacos , HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Resultado do Tratamento , Carga Viral
11.
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
13.
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
14.
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
15.
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
16.
Gene ; 792: 145735, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34048875

RESUMO

Human immunodeficiency virus (HIV) infection causes acquired immunodeficiency syndrome (AIDS), one of the most devastating diseases affecting humankind. Here, we have proposed a framework to examine the differences among microarray gene expression data of uninfected and three different HIV-1 infection stages using module preservation statistics. We leverage the advantage of gene co-expression networks (GCN) constructed for each infection stages to detect the topological and structural changes of a group of differentially expressed genes. We examine the relationship among a set of co-expression modules by constructing a module eigengene network considering the overall similarity/dissimilarity among the genes within the modules. We have utilized different module preservation statistics with two composite statistics: "Zsummary" and "MedianRank" to examine the changes in co-expression patterns between modules. We have found several interesting results on the preservation characteristics of gene modules across different stages. Some genes are identified to be preserved in a pair of stages while altering their characteristics across other stages. We further validated the obtained results using permutation test and classification techniques. The biological significances of the obtained modules have also been examined using gene ontology and pathway-based analysis. Additionally, we have identified a set of key immune regulatory hub genes in the associated protein-protein interaction networks (PPINs) of the differentially expressed (DE) genes, which interacts with HIV-1 proteins and are likely to act as potential biomarkers in HIV-1 progression.


Assuntos
Antígenos CD/genética , Quimiocinas/genética , Infecções por HIV/genética , HIV-1/patogenicidade , Interações Hospedeiro-Patógeno/genética , Proteínas do Vírus da Imunodeficiência Humana/genética , Doença Aguda , Antígenos CD/classificação , Antígenos CD/imunologia , Quimiocinas/classificação , Quimiocinas/imunologia , Doença Crônica , Conjuntos de Dados como Assunto , Progressão da Doença , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Infecções por HIV/imunologia , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/crescimento & desenvolvimento , Interações Hospedeiro-Patógeno/imunologia , Proteínas do Vírus da Imunodeficiência Humana/classificação , Proteínas do Vírus da Imunodeficiência Humana/imunologia , Humanos , Análise em Microsséries , Anotação de Sequência Molecular , Ligação Proteica , Transdução de Sinais
17.
Nat Commun ; 12(1): 2475, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931637

RESUMO

An innovative approach to eliminate HIV-1-infected cells emerging out of latency, the major hurdle to HIV-1 cure, is to pharmacologically reactivate viral expression and concomitantly trigger intracellular pro-apoptotic pathways in order to selectively induce cell death (ICD) of infected cells, without reliance on the extracellular immune system. In this work, we demonstrate the effect of DDX3 inhibitors on selectively inducing cell death in latent HIV-1-infected cell lines, primary CD4+ T cells and in CD4+ T cells from cART-suppressed people living with HIV-1 (PLWHIV). We used single-cell FISH-Flow technology to characterise the contribution of viral RNA to inducing cell death. The pharmacological targeting of DDX3 induced HIV-1 RNA expression, resulting in phosphorylation of IRF3 and upregulation of IFNß. DDX3 inhibition also resulted in the downregulation of BIRC5, critical to cell survival during HIV-1 infection, and selectively induced apoptosis in viral RNA-expressing CD4+ T cells but not bystander cells. DDX3 inhibitor treatment of CD4+ T cells from PLWHIV resulted in an approximately 50% reduction of the inducible latent HIV-1 reservoir by quantitation of HIV-1 RNA, by FISH-Flow, RT-qPCR and TILDA. This study provides proof of concept for pharmacological reversal of latency coupled to induction of apoptosis towards the elimination of the inducible reservoir.


Assuntos
Apoptose/efeitos dos fármacos , Azepinas/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , RNA Helicases DEAD-box/metabolismo , Infecções por HIV/imunologia , HIV-1/metabolismo , Imidazóis/farmacologia , Latência Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Antirretrovirais/farmacologia , Apoptose/genética , Azepinas/química , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , RNA Helicases DEAD-box/antagonistas & inibidores , RNA Helicases DEAD-box/química , Inibidores Enzimáticos/farmacologia , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Imidazóis/química , Hibridização in Situ Fluorescente , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/metabolismo , Células Jurkat , Simulação de Acoplamento Molecular , RNA Viral/metabolismo , Análise de Célula Única , Survivina/metabolismo , Ativação Viral/efeitos dos fármacos , Replicação Viral/genética
18.
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
19.
Med J Malaysia ; 76(3): 446-448, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34031352

RESUMO

Coronavirus Disease 2019 (COVID-19) is an acute respiratory infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection that started in Wuhan, China in December 2019 and has spread rapidly worldwide. It's critical to take extra precautions if a person has chronic illnesses (comorbidities), such as human immunodeficiency (HIV) infection. Concerns about people living with HIV (PLHIV) having a higher risk of serious COVID-19 disease may be based on the assumption that PLHIV are more likely to be immunocompromised. On the other hand, limited information is available in such people about the characteristics of co-infection between SARS-CoV-2 and Human Immunodeficiency Virus (HIV) who are at greater risk than the general population. Our findings, is of a 32 year old patient who came to Emergency Unit of Wangaya Hospital, Medical Faculty, Udayana University in Denpasar, Bali with complaint of fever, dry cough, and shortness of breath since prior 3 days and had also the past history prolonged fever, weight loss more than 10% 4 weeks. Diagnosis of COVID-19 was confirmed by nasopharyngeal swab sample was used for RT-PCR assay and PITC to confirm HIV infection. He had prolonged hospitalized and discharge after 18 days.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , COVID-19/diagnóstico , Coinfecção/diagnóstico , Infecções por HIV/diagnóstico , Adulto , Biomarcadores/sangue , COVID-19/sangue , COVID-19/imunologia , Coinfecção/sangue , Coinfecção/imunologia , Infecções por HIV/sangue , Infecções por HIV/imunologia , Humanos , Masculino
20.
Lancet HIV ; 8(7): e408-e419, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33915104

RESUMO

BACKGROUND: Pneumococcus remains an important cause of morbidity in pregnant women with HIV and their infants. We compared the safety and immunogenicity of PCV-10 and PPV-23 with placebo administered in pregnancy. METHODS: This double-blind, multicentre, randomised controlled trial was done at eight outpatient clinics in Brazil. Eligible participants were adult women with HIV who were pregnant at a gestational age between 14 weeks and less than 34 weeks and who were taking antiretroviral therapy at study entry. Participants were randomly assigned (1:1:1) to receive either PCV-10, PPV-23, or placebo. Participants and study teams were unaware of treatment allocation. Antibodies against seven vaccine serotypes in PCV-10 and PPV-23 were measured by ELISA. The primary outcomes were maternal and infant safety assessed by the frequency of adverse events of grade 3 or higher; maternal seroresponse (defined as ≥2-fold increase in antibodies from baseline to 28 days after immunisation) against five or more serotypes; and infant seroprotection (defined as anti-pneumococcus antibody concentration of ≥0·35 µg/mL) against five or more serotypes at 8 weeks of life. The study was powered to detect differences of 20% or higher in the primary immunological outcomes between treatment groups. This trial is registered with ClinicalTrials.gov, NCT02717494. FINDINGS: Between April 1, 2016, and Nov 30, 2017, we enrolled 347 pregnant women with HIV, of whom 116 were randomly assigned to the PCV-10 group, 115 to the PPV-23 group, and 116 to the placebo group. One participant in the PCV-10 group did not receive the vaccine and was excluded from subsequent analyses. The frequency of adverse events of grade 3 or higher during the first 4 weeks was similar in the vaccine and placebo groups (3% [90% CI 1-7] for the PCV-10 group, 2% [0-5] for the PPV-23 group, and 3% [1-8] for the placebo group). However, injection site and systemic grade 2 adverse reactions were reported more frequently during the first 4 weeks in the vaccine groups than in the placebo group (14% [9-20] for the PCV-10 group, 7% [4-12] for the PPV-23 group, and 3% [1-7] for the placebo group). The frequency of grade 3 or higher adverse effects was similar across maternal treatment groups (20% [14-27] for the PCV-10 group, 21% [14-28] for the PPV-23 group, and 20% [14-27] for the placebo group). Seroresponses against five or more serotypes were present in 74 (65%) of 114 women in the PCV-10 group, 72 (65%) of 110 women in the PPV-23 group, and none of the 113 women in the placebo group at 4 weeks post vaccination (p<0·0001 for PPV-23 group vs placebo and PCV-10 group vs placebo). Seroresponse differences of 20% or higher in vaccine compared with placebo recipients persisted up to 24 weeks post partum. At birth, 76 (67%) of 113 infants in the PCV-10 group, 62 (57%) of 109 infants in the PPV-23 group, and 19 (17%) of 115 infants in the placebo group had seroprotection against five or more serotypes (p<0·0001 for PPV-23 vs placebo and PCV-10 vs placebo). At 8 weeks, the outcome was met by 20 (19%) of 108 infants in the PCV-10 group, 24 (23%) of 104 infants in the PPV-23 group, and one (1%) of 109 infants in the placebo group (p<0·0001). Although a difference of 20% or higher compared with placebo was observed only in the infants who received PPV-23 at 8 weeks of life, the difference between the two vaccine groups was not appreciable. INTERPRETATION: PCV-10 and PPV-23 were equally safe and immunogenic in pregnant women with HIV and conferred similar levels of seroprotection to their infants. In areas in which childhood PCV administration decreased the circulation of PCV serotypes, PPV-23 administration to pregnant women with HIV might be more advantageous than PCV by virtue of including a broader range of serotypes. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.


Assuntos
Anticorpos Antibacterianos/imunologia , Infecções por HIV/complicações , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/administração & dosagem , Adulto , Fármacos Anti-HIV/uso terapêutico , Brasil , Método Duplo-Cego , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Lactente , Recém-Nascido , Masculino , Placenta/imunologia , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Vacinas Pneumocócicas/efeitos adversos , Gravidez , Gestantes , Streptococcus pneumoniae/imunologia , Adulto Jovem
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