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1.
Biomed Res Int ; 2021: 5599588, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34513993

RESUMO

Background: Despite being sexually active and engaging in risky sexual behaviours similar to young adults, older adults (50 years or older) are less likely to receive HIV testing, and disaggregated data are still scarce about HIV prevention and treatment in this vulnerable population in sub-Saharan Africa (SSA). This systematic review is aimed at examining sex differences in HIV testing and counseling (HTC) among older adults in SSA. Methods: A systematic search of four databases, namely, MEDLINE (Ovid), EMBASE (Ovid), Web of Science, and Global Health, was conducted from 2000 to January 2020. The primary outcome of interest for this study was gender differences in HTC among older adults in SSA. Observational studies including cross-sectional, retrospective, and prospective cohort studies were included. Eligible studies must have reported sex differences in HIV testing uptake in a standard HTC service among older adults in SSA. Results: From the database search, 4143 articles were identified. Five studies were ultimately included in the final review. Of the 1189 participants, 606 (51.1%) and 580 (48.9%) were female and male, respectively. The review findings suggested that both men and women preferred HTC providers that are the same sex as them with women additionally preferring a provider who is also of a similar age. Men and women differed in their pathways to getting tested for HIV. The review documented mixed results with regard to the associations between sex of older adults and uptake of HTC. Older adult HTC uptake data are limited in scope and coverage in sub-Saharan Africa. Conclusion: This review revealed shortage of evidence to evaluate optimum HTC utilization among older adults. Few studies examined sex differences in HIV testing among older adults in the region. There is a need for stakeholders working in the area of HIV prevention and treatment to focus on older adult health utilization evidence organization, disaggregated by age and sex. Hence, high-quality research designs are needed on the topic in order to generate good quality evidence for targeted interventions to improve HTC among older adults in sub-Saharan Africa.


Assuntos
Infecções por HIV/psicologia , Teste de HIV/tendências , Comportamento Sexual/psicologia , África ao Sul do Saara/epidemiologia , Idoso , Aconselhamento , Estudos Transversais , Bases de Dados Factuais , Feminino , Infecções por HIV/prevenção & controle , Teste de HIV/ética , Teste de HIV/métodos , HIV-1/patogenicidade , Comportamentos de Risco à Saúde/ética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Caracteres Sexuais , Fatores Sexuais
2.
Viruses ; 13(7)2021 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-34372547

RESUMO

In individuals infected with hepatitis B virus (HBV), the loss of hepatitis B surface antigen (HBsAg) is the ultimate therapeutic goal, which defines "functional cure." For individuals living with human immunodeficiency virus (HIV), functional cure occurs roughly 2 per 100 person-years during potent anti-HBV containing antiretroviral therapy. Although this rate may be higher than expected in treated HBV mono-infected individuals, rates of functional cure widely vary between studies (0.6-10.5 per 100 person-years). Similar to HBV mono-infection, the phase of HBV infection, HBV (sub-)genotypes and hepatitis B "e" Ag-negative variants are associated with functional cure in treated HIV-HBV co-infection. In specifically HIV-HBV co-infected individuals, strong increases in CD4+ T cell counts after treatment initiation have also been linked to functional cure, yet this finding is inconsistent across studies. Several markers directly or indirectly reflecting HBV activity are being developed to predict functional cure, such as quantification of HBsAg, hepatitis B core-related antigen, HBsAg protein composition, anti-hepatitis B core antibodies and interferon-gamma-inducible protein 10. Few have been assessed during treatment in HIV-HBV co-infected individuals and none have been validated to predict functional cure. Novel therapeutics for HBV cure are essential for individuals with HIV-HBV co-infection and need to be separately evaluated in this population.


Assuntos
Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/fisiopatologia , Infecções por HIV/virologia , HIV-1/patogenicidade , Hepatite B/complicações , Hepatite B/fisiopatologia , Anticorpos Anti-Hepatite B/imunologia , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/fisiopatologia , Humanos
3.
Viruses ; 13(7)2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34372560

RESUMO

The combination of the two nucleoside reverse transcriptase inhibitors (NRTI) tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is used in most highly active antiretroviral therapies for treatment of HIV-1 infection, as well as in pre-exposure prophylaxis against HIV acquisition. Administered as prodrugs, these drugs are taken up by HIV-infected target cells, undergo intracellular phosphorylation and compete with natural deoxynucleoside triphosphates (dNTP) for incorporation into nascent viral DNA during reverse transcription. Once incorporated, they halt reverse transcription. In vitro studies have proposed that TDF and FTC act synergistically within an HIV-infected cell. However, it is unclear whether, and which, direct drug-drug interactions mediate the apparent synergy. The goal of this work was to refine a mechanistic model for the molecular mechanism of action (MMOA) of nucleoside analogues in order to analyse whether putative direct interactions may account for the in vitro observed synergistic effects. Our analysis suggests that depletion of dNTP pools can explain apparent synergy between TDF and FTC in HIV-infected cells at clinically relevant concentrations. Dead-end complex (DEC) formation does not seem to significantly contribute to the synergistic effect. However, in the presence of non-nucleoside reverse transcriptase inhibitors (NNRTIs), its role might be more relevant, as previously reported in experimental in vitro studies.


Assuntos
Emtricitabina/uso terapêutico , HIV-1/efeitos dos fármacos , Tenofovir/uso terapêutico , Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade/métodos , Desoxicitidina/análogos & derivados , Quimioterapia Combinada/métodos , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/genética , HIV-1/patogenicidade , Humanos , Modelos Teóricos , Profilaxia Pré-Exposição/métodos , Transcrição Reversa/efeitos dos fármacos , Tenofovir/metabolismo
4.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360591

RESUMO

FREM1 (Fras-related extracellular matrix 1) and its splice variant TILRR (Toll-like interleukin-1 receptor regulator) have been identified as integral components of innate immune systems. The potential involvement of FREM1 in HIV-1 (human immunodeficiency virus 1) acquisition was suggested by a genome-wide SNP (single nucleotide polymorphism) analysis of HIV-1 resistant and susceptible sex workers enrolled in the Pumwani sex worker cohort (PSWC) in Nairobi, Kenya. The studies showed that the minor allele of a FREM1 SNP rs1552896 is highly enriched in the HIV-1 resistant female sex workers. Subsequent studies showed that FREM1 mRNA is highly expressed in tissues relevant to mucosal HIV-1 infection, including cervical epithelial tissues, and TILRR is a major modulator of many genes in the NF-κB signal transduction pathway. In this article, we review the role of FREM1 and TILRR in modulating inflammatory responses and inflammation, and how their influence on inflammatory responses of cervicovaginal tissue could enhance the risk of vaginal HIV-1 acquisition.


Assuntos
Infecções por HIV/virologia , HIV-1/patogenicidade , Inflamação/complicações , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/metabolismo , Profissionais do Sexo/estatística & dados numéricos , Vagina/virologia , Feminino , Infecções por HIV/epidemiologia , Humanos , Isoformas de Proteínas , Receptores de Interleucina/genética
5.
Biochim Biophys Acta Mol Basis Dis ; 1867(12): 166244, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34411716

RESUMO

The placenta provides a significant physical and physiological barrier to prevent fetal infection during pregnancy. Nevertheless, it is at times breached by pathogens and leads to vertical transmission of infection from mother to fetus. This review will focus specifically on the Zika flavivirus, the HIV retrovirus and the emerging SARS-CoV2 coronavirus, which have affected pregnant women and their offspring in recent epidemics. In particular, we will address how viral infections affect the immune response at the maternal-fetal interface and how the placental barrier is physically breached and discuss the consequences of infection on various aspects of placental function to support fetal growth and development. Improved understanding of how the placenta responds to viral infections will lay the foundation for developing therapeutics to these and emergent viruses, to minimise the harms of infection to the offspring.


Assuntos
Placenta/virologia , Complicações Infecciosas na Gravidez/virologia , Viroses/fisiopatologia , COVID-19/metabolismo , Feminino , Feto/virologia , Infecções por HIV/metabolismo , HIV-1/patogenicidade , Humanos , Transmissão Vertical de Doenças Infecciosas/estatística & dados numéricos , Placenta/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , SARS-CoV-2/patogenicidade , Zika virus/patogenicidade , Infecção por Zika virus/metabolismo
6.
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
7.
Nat Commun ; 12(1): 3727, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140517

RESUMO

Clonal expansion of HIV-infected cells contributes to the long-term persistence of the HIV reservoir in ART-suppressed individuals. However, the contribution from cell clones that harbor inducible proviruses to plasma viremia is poorly understood. Here, we describe a single-cell approach to simultaneously sequence the TCR, integration sites and proviral genomes from translation-competent reservoir cells, called STIP-Seq. By applying this approach to blood samples from eight participants, we show that the translation-competent reservoir mainly consists of proviruses with short deletions at the 5'-end of the genome, often involving the major splice donor site. TCR and integration site sequencing reveal that cell clones with predicted pathogen-specificity can harbor inducible proviruses integrated into cancer-related genes. Furthermore, we find several matches between proviruses retrieved with STIP-Seq and plasma viruses obtained during ART and upon treatment interruption, suggesting that STIP-Seq can capture clones that are responsible for low-level viremia or viral rebound.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , HIV-1/metabolismo , Provírus/genética , Análise de Célula Única/métodos , Viremia/virologia , Linfócitos T CD4-Positivos/virologia , DNA Viral/sangue , Infecções por HIV/virologia , HIV-1/genética , HIV-1/patogenicidade , Humanos , Ionomicina/farmacologia , Masculino , Pessoa de Meia-Idade , Filogenia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Deleção de Sequência , Carga Viral/genética
8.
Nat Commun ; 12(1): 3691, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140527

RESUMO

The HIV-1 accessory proteins Vif, Vpu, and Nef can promote infection by overcoming the inhibitory effects of the host cell restriction factors APOBEC3G, Tetherin, and SERINC5, respectively. However, how the HIV-1 accessory protein Vpr enhances infection in macrophages but not in CD4+ T cells remains elusive. Here, we report that Vpr counteracts lysosomal-associated transmembrane protein 5 (LAPTM5), a potent inhibitor of HIV-1 particle infectivity, to enhance HIV-1 infection in macrophages. LAPTM5 transports HIV-1 envelope glycoproteins to lysosomes for degradation, thereby inhibiting virion infectivity. Vpr counteracts the restrictive effects of LAPTM5 by triggering its degradation via DCAF1. In the absence of Vpr, the silencing of LAPTM5 precisely phenocopied the effect of Vpr on HIV-1 infection. In contrast, Vpr did not enhance HIV-1 infection in the absence of LAPTM5. Moreover, LAPTM5 was highly expressed in macrophages but not in CD4+ T lymphocytes. Re-expressing LAPTM5 reconstituted the Vpr-dependent promotion of HIV-1 infection in primary CD4+ T cells, as observed in macrophages. Herein, we demonstrate the molecular mechanism used by Vpr to overcome LAPTM5 restriction in macrophages, providing a potential strategy for anti-HIV/AIDS therapeutics.


Assuntos
Infecções por HIV/metabolismo , HIV-1/metabolismo , Interações entre Hospedeiro e Microrganismos , Macrófagos/metabolismo , Macrófagos/virologia , Proteínas de Membrana/metabolismo , Produtos do Gene vpr do Vírus da Imunodeficiência Humana/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Inativação Gênica , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/genética , HIV-1/patogenicidade , HIV-2/metabolismo , HIV-2/patogenicidade , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Lisossomos/metabolismo , Proteínas de Membrana/genética , Estabilidade Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Vírus da Imunodeficiência Símia/metabolismo , Vírus da Imunodeficiência Símia/patogenicidade , Ubiquitina-Proteína Ligases/metabolismo , Regulação para Cima , Vírion/metabolismo
9.
Front Immunol ; 12: 625649, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093520

RESUMO

Genital mucosal transmission is the most common route of HIV spread. The initial responses triggered at the site of viral entry are reportedly affected by host factors, especially complement components present at the site, and this will have profound consequences on the outcome and pathogenesis of HIV infection. We studied the initial events associated with host-pathogen interactions by exposing cervical biopsies to free or complement-opsonized HIV. Opsonization resulted in higher rates of HIV acquisition/infection in mucosal tissues and emigrating dendritic cells. Transcriptomic and proteomic data showed a significantly more pathways and higher expression of genes and proteins associated with viral replication and pathways involved in different aspects of viral infection including interferon signaling, cytokine profile and dendritic cell maturation for the opsonized HIV. Moreover, the proteomics data indicate a general suppression by the HIV exposure. This clearly suggests that HIV opsonization alters the initial signaling pathways in the cervical mucosa in a manner that promotes viral establishment and infection. Our findings provide a foundation for further studies of the role these early HIV induced events play in HIV pathogenesis.


Assuntos
Colo do Útero/virologia , Proteínas do Sistema Complemento/imunologia , Perfilação da Expressão Gênica , Infecções por HIV/virologia , HIV-1/patogenicidade , Membrana Mucosa/virologia , Proteoma , Proteômica , Transcriptoma , Colo do Útero/imunologia , Colo do Útero/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/virologia , Feminino , Regulação da Expressão Gênica , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , HIV-1/crescimento & desenvolvimento , HIV-1/imunologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Membrana Mucosa/imunologia , Membrana Mucosa/metabolismo , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/virologia , Fatores de Tempo , Técnicas de Cultura de Tecidos , Internalização do Vírus , Replicação Viral
12.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069929

RESUMO

The success of antiretroviral treatment (ART) is threatened by the emergence of drug resistance mutations (DRM). Since Brazil presents the largest number of people living with HIV (PLWH) in South America we aimed at understanding the dynamics of DRM in this country. We analyzed a total of 20,226 HIV-1 sequences collected from PLWH undergoing ART between 2008-2017. Results show a mild decline of DRM over the years but an increase of the K65R reverse transcriptase mutation from 2.23% to 12.11%. This increase gradually occurred following alterations in the ART regimens replacing zidovudine (AZT) with tenofovir (TDF). PLWH harboring the K65R had significantly higher viral loads than those without this mutation (p < 0.001). Among the two most prevalent HIV-1 subtypes (B and C) there was a significant (p < 0.001) association of K65R with subtype C (11.26%) when compared with subtype B (9.27%). Nonetheless, evidence for K65R transmission in Brazil was found both for C and B subtypes. Additionally, artificial neural network-based immunoinformatic predictions suggest that K65R could enhance viral recognition by HLA-B27 that has relatively low prevalence in the Brazilian population. Overall, the results suggest that tenofovir-based regimens need to be carefully monitored particularly in settings with subtype C and specific HLA profiles.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/genética , Adenina/uso terapêutico , Adulto , Idoso , Fármacos Anti-HIV/farmacologia , Brasil/epidemiologia , Farmacorresistência Viral/fisiologia , Feminino , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Tenofovir/uso terapêutico , Falha de Tratamento , Carga Viral/efeitos dos fármacos , Zidovudina/uso terapêutico
13.
Int J Mol Sci ; 22(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068829

RESUMO

Cassia abbreviata is widely used in Sub-Saharan Africa for treating many diseases, including HIV-1 infection. We have recently described the chemical structures of 28 compounds isolated from an alcoholic crude extract of barks and roots of C. abbreviata, and showed that six bioactive compounds inhibit HIV-1 infection. In the present study, we demonstrate that the six compounds block HIV-1 entry into cells: oleanolic acid, palmitic acid, taxifolin, piceatannol, guibourtinidol-(4α→8)-epiafzelechin, and a novel compound named as cassiabrevone. We report, for the first time, that guibourtinidol-(4α→8)-epiafzelechin and cassiabrevone inhibit HIV-1 entry (IC50 of 42.47 µM and 30.96 µM, respectively), as well as that piceatannol interacts with cellular membranes. Piceatannol inhibits HIV-1 infection in a dual-chamber assay mimicking the female genital tract, as well as HSV infection, emphasizing its potential as a microbicide. Structure-activity relationships (SAR) showed that pharmacophoric groups of piceatannol are strictly required to inhibit HIV-1 entry. By a ligand-based in silico study, we speculated that piceatannol and norartocarpetin may have a very similar mechanism of action and efficacy because of the highly comparable pharmacophoric and 3D space, while guibourtinidol-(4α→8)-epiafzelechin and cassiabrevone may display a different mechanism. We finally show that cassiabrevone plays a major role of the crude extract of CA by blocking the binding activity of HIV-1 gp120 and CD4.


Assuntos
Cassia/química , Infecções por HIV/tratamento farmacológico , Extratos Vegetais/farmacologia , Internalização do Vírus/efeitos dos fármacos , Catequina/farmacologia , Proteína gp120 do Envelope de HIV/genética , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Humanos , Ácido Oleanólico/farmacologia , Ácido Palmítico/farmacologia , Extratos Vegetais/química , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/genética , Raízes de Plantas/virologia , Quercetina/análogos & derivados , Quercetina/farmacologia , Estilbenos/farmacologia
14.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073578

RESUMO

Ceramide is a lipid messenger at the heart of sphingolipid metabolism. In concert with its metabolizing enzymes, particularly sphingomyelinases, it has key roles in regulating the physical properties of biological membranes, including the formation of membrane microdomains. Thus, ceramide and its related molecules have been attributed significant roles in nearly all steps of the viral life cycle: they may serve directly as receptors or co-receptors for viral entry, form microdomains that cluster entry receptors and/or enable them to adopt the required conformation or regulate their cell surface expression. Sphingolipids can regulate all forms of viral uptake, often through sphingomyelinase activation, and mediate endosomal escape and intracellular trafficking. Ceramide can be key for the formation of viral replication sites. Sphingomyelinases often mediate the release of new virions from infected cells. Moreover, sphingolipids can contribute to viral-induced apoptosis and morbidity in viral diseases, as well as virus immune evasion. Alpha-galactosylceramide, in particular, also plays a significant role in immune modulation in response to viral infections. This review will discuss the roles of ceramide and its related molecules in the different steps of the viral life cycle. We will also discuss how novel strategies could exploit these for therapeutic benefit.


Assuntos
Ceramidas/metabolismo , HIV-1/metabolismo , Vírus da Influenza A/metabolismo , SARS-CoV-2/metabolismo , Viroses/metabolismo , Viroses/virologia , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Ceramidas/química , Regulação Viral da Expressão Gênica , HIV-1/patogenicidade , Humanos , Imunomodulação , Vírus da Influenza A/patogenicidade , SARS-CoV-2/patogenicidade , Vírion/crescimento & desenvolvimento , Viroses/imunologia , Internalização do Vírus , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologia
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.
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.
Nucleic Acids Res ; 49(10): 5925-5942, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33978756

RESUMO

HIV-1 reverse transcription initiates at the primer binding site (PBS) in the viral genomic RNA (gRNA). Although the structure of the PBS-segment undergoes substantial rearrangement upon tRNALys3 annealing, the proper folding of the PBS-segment during gRNA packaging is important as it ensures loading of beneficial host factors. DHX9/RNA helicase A (RHA) is recruited to gRNA to enhance the processivity of reverse transcriptase. Because the molecular details of the interactions have yet to be defined, we solved the solution structure of the PBS-segment preferentially bound by RHA. Evidence is provided that PBS-segment adopts a previously undefined adenosine-rich three-way junction structure encompassing the primer activation stem (PAS), tRNA-like element (TLE) and tRNA annealing arm. Disruption of the PBS-segment three-way junction structure diminished reverse transcription products and led to reduced viral infectivity. Because of the existence of the tRNA annealing arm, the TLE and PAS form a bent helical structure that undergoes shape-dependent recognition by RHA double-stranded RNA binding domain 1 (dsRBD1). Mutagenesis and phylogenetic analyses provide evidence for conservation of the PBS-segment three-way junction structure that is preferentially bound by RHA in support of efficient reverse transcription, the hallmark step of HIV-1 replication.


Assuntos
RNA Helicases DEAD-box/química , HIV-1/química , Proteínas de Neoplasias/química , RNA Viral/química , Transcrição Reversa/genética , Replicação Viral/genética , Regiões 5' não Traduzidas , Sítios de Ligação/genética , Linhagem Celular , HIV-1/genética , HIV-1/patogenicidade , Humanos , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Mutação , Conformação de Ácido Nucleico , Motivos de Nucleotídeos , Filogenia , Conformação Proteica em alfa-Hélice , Domínios Proteicos , RNA de Transferência de Lisina/genética , RNA de Transferência de Lisina/metabolismo , RNA Viral/genética
18.
J Virol ; 95(16): e0058821, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34037423

RESUMO

Serine incorporator 5 (SERINC5) reduces the infectivity of progeny HIV-1 virions by incorporating into the outer host-derived viral membrane during egress. To counter SERINC5, the HIV-1 accessory protein Nef triggers SERINC5 internalization by engaging the adaptor protein 2 (AP-2) complex using the [D/E]xxxL[L/I]167 Nef dileucine motif. Nef also engages AP-2 via its dileucine motif to downregulate the CD4 receptor. Although these two Nef functions are related, the mechanisms governing SERINC5 downregulation are incompletely understood. Here, we demonstrate that two primary Nef isolates, referred to as 2410 and 2391 Nef, acquired from acutely HIV-1 infected women from Zimbabwe, both downregulate CD4 from the cell surface. However, only 2410 Nef retains the ability to downregulate cell surface SERINC5. Using a series of Nef chimeras, we mapped the region of 2391 Nef responsible for the functional uncoupling of these two antagonistic pathways to the dileucine motif. Modifications of the first and second x positions of the 2410 Nef dileucine motif to asparagine and aspartic acid residues, respectively (ND164), impaired cell surface SERINC5 downregulation, which resulted in reduced infectious virus yield in the presence of SERINC5. The ND164 mutation additionally partially impaired, but did not completely abrogate, Nef-mediated cell surface CD4 downregulation. Furthermore, the patient infected with HIV-1 encoding 2391 Nef had stable CD4+ T cell counts, whereas infection with HIV-1 encoding 2410 Nef resulted in CD4+ T cell decline and disease progression. IMPORTANCE A contributing factor to HIV-1 persistence is evasion of the host immune response. HIV-1 uses the Nef accessory protein to evade the antiviral roles of the adaptive and intrinsic innate immune responses. Nef targets SERINC5, a restriction factor which potently impairs HIV-1 infection by triggering SERINC5 removal from the cell surface. The molecular determinants underlying this Nef function remain incompletely understood. Recent studies have found a correlation between the extent of Nef-mediated SERINC5 downregulation and the rate of disease progression. Furthermore, single-residue polymorphisms outside the known Nef functional motifs can modulate SERINC5 downregulation. The identification of a naturally occurring Nef polymorphism impairing SERINC5 downregulation in this study supports a link between Nef downregulation of SERINC5 and the rate of plasma CD4+ T cell decline. Moreover, the observed functional impairments of this polymorphism could provide clues to further elucidate unknown aspects of the SERINC5 antagonistic pathway via Nef.


Assuntos
Antígenos CD4/metabolismo , Infecções por HIV/virologia , HIV-1/patogenicidade , Proteínas de Membrana/metabolismo , Produtos do Gene nef do Vírus da Imunodeficiência Humana/fisiologia , Motivos de Aminoácidos , Linfócitos T CD4-Positivos/patologia , Progressão da Doença , Regulação para Baixo , Feminino , Infecções por HIV/metabolismo , HIV-1/genética , Humanos , Mutação , Polimorfismo Genético , Vírion , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética , Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo
19.
Lancet HIV ; 8(5): e266-e273, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33891877

RESUMO

BACKGROUND: There are few data on life expectancy gains among people living with HIV in low-income and middle-income settings where antiretroviral therapy (ART) is increasingly available. We aimed to analyse life expectancy trends from 2003 to 2017 among people with HIV beginning treatment with ART within the Caribbean, central America, and South America. METHODS: We did a multisite retrospective cohort study and included people with HIV who had started treatment with ART and were aged 16 years or older between Jan 1, 2003, and Dec 31, 2017, from Caribbean, Central and South America network for HIV epidemiology (CCASAnet) sites in Argentina, Brazil, Chile, Haiti, Honduras, Mexico, and Peru, who contributed person-time data from the age of 20 years until date of death, last contact, database closure, or Dec 31, 2017. We used the Chiang method of abridged life tables to estimate life expectancy at age 20 years for three eras (2003-08, 2009-12, and 2013-17) overall and by demographic and clinical characteristics at ART initiation. We used Poisson regression models to weight mortality rates to account for informative censoring. FINDINGS: 30 688 people with HIV were included in the study; 17 491 (57·0%) were from the Haiti site and 13 197 (43·0%) were from all other sites. There were 2637 deaths during the study period: 1470 in Haiti and 1167 in other sites. Crude and weighted mortality rates decreased among all age groups over calendar eras. From 2003-08 to 2013-17, overall life expectancy for people with HIV at age 20 years increased from 13·9 years (95% CI 12·5-15·2) to 61·2 years (59·0-63·4) in Haiti and from 31·0 years (29·3-32·8) to 69·5 years (67·2-71·8) in other sites. Life expectancies at the end of the study period were within 10 years of those of the general population (69·9 years in Haiti and 78·0 years in all other sites in 2018). Disparities in life expectancy among people with HIV by sex or HIV transmission risk factor, CD4 cell count, level of education, and history of tuberculosis at or before ART initiation persisted across calendar eras. INTERPRETATION: Life expectancy among people with HIV receiving ART has significantly improved in Latin America and the Caribbean. Persistent disparities in life expectancy among people with HIV by demographic and clinical factors at ART initiation highlight vulnerable populations in the region. FUNDING: National Institutes of Health. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Expectativa de Vida/tendências , RNA Viral/antagonistas & inibidores , Adolescente , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade , Região do Caribe/epidemiologia , Feminino , Infecções por HIV/mortalidade , Infecções por HIV/transmissão , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , HIV-1/patogenicidade , Humanos , América Latina/epidemiologia , Masculino , Pessoa de Meia-Idade , RNA Viral/genética , Estudos Retrospectivos , Risco , Análise de Sobrevida , Carga Viral/efeitos dos fármacos
20.
J Virol ; 95(13): e0217720, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-33883222

RESUMO

Molecular interactions of the variable envelope gp120 subunit of HIV-1 with two cellular receptors are the first step of viral infection, thereby playing pivotal roles in determining viral infectivity and cell tropism. However, the underlying regulatory mechanisms for interactions under gp120 spontaneous variations largely remain unknown. Here, we show an allosteric mechanism in which a single gp120 mutation remotely controls the ternary interactions between gp120 and its receptors for the switch of viral cell tropism. Virological analyses showed that a G310R substitution at the tip of the gp120 V3 loop selectively abolished the viral replication ability in human cells, despite evoking enhancement of viral replication in macaque cells. Molecular dynamics (MD) simulations predicted that the G310R substitution at a site away from the CD4 interaction site selectively impeded the binding ability of gp120 to human CD4. Consistently, virions with the G310R substitution exhibited a reduced binding ability to human lymphocyte cells. Furthermore, the G310R substitution influenced the gp120-CCR5 interaction in a CCR5-type dependent manner as assessed by MD simulations and an infectivity assay using exogenously expressed CCR5s. Interestingly, an I198M mutation in human CCR5 restored the infectivity of the G310R virus in human cells. Finally, MD simulation predicted amino acid interplays that physically connect the V3 loop and gp120 elements for the CD4 and CCR5 interactions. Collectively, these results suggest that the V3 loop tip is a cis-allosteric regulator that remotely controls intra- and intermolecular interactions of HIV-1 gp120 for balancing ternary interactions with CD4 and CCR5. IMPORTANCE Understanding the molecular bases for viral entry into cells will lead to the elucidation of one of the major viral survival strategies, and thus to the development of new effective antiviral measures. As shown recently, HIV-1 is highly mutable and adaptable in growth-restrictive cells, such as those of macaque origin. HIV-1 initiates its infection by sequential interactions of Env-gp120 with two cell surface receptors, CD4 and CCR5. A recent epoch-making structural study has disclosed that CD4-induced conformation of gp120 is stabilized upon binding of CCR5 to the CD4-gp120 complex, whereas the biological significance of this remains totally unknown. Here, from a series of mutations found in our extensive studies, we identified a single-amino acid adaptive mutation at the V3 loop tip of Env-gp120 critical for its interaction with both CD4 and CCR5 in a host cell species-specific way. This remarkable finding could certainly provoke and accelerate studies to precisely clarify the HIV-1 entry mechanism.


Assuntos
Proteína gp120 do Envelope de HIV/genética , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/genética , Receptores Virais/metabolismo , Tropismo Viral/genética , Substituição de Aminoácidos/genética , Animais , Antígenos CD4/metabolismo , Linhagem Celular , Células HEK293 , HIV-1/patogenicidade , Células HeLa , Humanos , Linfócitos/virologia , Macaca fascicularis , Simulação de Dinâmica Molecular , Receptores CCR5/metabolismo , Especificidade da Espécie
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