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1.
Artigo em Inglês | MEDLINE | ID: mdl-37126090

RESUMO

Since the first HIV-cured person was reported in 2009, a strong interest in developing highly sensitive HIV and SIV reservoir assays has emerged. In particular, the question arose about the comparative value of state-of-the-art assays to measure and characterize the HIV reservoir, and how these assays can be applied to accurately detect changes in the reservoir during efforts to develop a cure for HIV infection. Second, it is important to consider the impact on the outcome of clinical trials if these relatively new HIV reservoir assays are incorporated into clinical trial endpoints and/or used for clinical decision-making. To understand the advantages and limitations and the regulatory implications of HIV reservoir assays, the National Institute of Allergy and Infectious Diseases (NIAID) sponsored and convened a meeting on September 16, 2022, to discuss the state of knowledge concerning these questions and best practices for selecting HIV reservoir assays for a particular research question or clinical trial protocol.

2.
Curr HIV Res ; 18(1): 19-28, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31870268

RESUMO

The main advantage of animal models of infectious diseases over in vitro studies is the gain in the understanding of the complex dynamics between the immune system and the pathogen. While small animal models have practical advantages over large animal models, it is crucial to be aware of their limitations. Although the small animal model at least needs to be susceptible to the pathogen under study to obtain meaningful data, key elements of pathogenesis should also be reflected when compared to humans. Well-designed small animal models for HIV, hepatitis viruses and tuberculosis require, additionally, a thorough understanding of the similarities and differences in the immune responses between humans and small animals and should incorporate that knowledge into the goals of the study. To discuss these considerations, the NIAID hosted a workshop on 'Small Animal Models for HIV, Hepatitis B, and Tuberculosis' on May 30, 2019. Highlights of the workshop are outlined below.


Assuntos
Modelos Animais de Doenças , Infecções por HIV/patologia , HIV-1/imunologia , Vírus da Hepatite B/imunologia , Hepatite B/patologia , Mycobacterium tuberculosis/imunologia , Tuberculose/patologia , Animais , Coinfecção/microbiologia , Cobaias , Infecções por HIV/imunologia , Hepatite B/imunologia , Humanos , Macaca mulatta , Marmota , Camundongos , National Institute of Allergy and Infectious Diseases (U.S.) , Coelhos , Tuberculose/imunologia , Estados Unidos
3.
AIDS Res Hum Retroviruses ; 34(1): 12-26, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29145733

RESUMO

Advances in imaging technologies have greatly increased our understanding of cellular and molecular interactions in humans and their corresponding animal models of infectious diseases. In the HIV/SIV field, imaging has provided key insights into mucosal viral transmission, local and systemic virus spread, host-virus dynamics, and chronic inflammation/immune activation and the resultant immunopathology. Recent developments in imaging applications are yielding physical, spatial, and temporal measurements to enhance insight into biological functions and disease processes, while retaining important cellular, microenvironmental, organ, and intact organism contextual details. Taking advantage of the latest advancements in imaging technologies may help answer important questions in the HIV field. The Global HIV Vaccine Enterprise in collaboration with the National Institutes of Health (NIH) sponsored a meeting on May 8 and 9, 2017 to provide a platform to review state-of-the-art imaging technologies and to foster multidisciplinary collaborations in HIV/AIDS research. The meeting covered applications of imaging in studies of early events and pathogenesis, reservoirs, and cure, as well as in vaccine development. In addition, presentations and discussions of imaging applications from non-HIV biomedical research areas were included. This report summarizes the presentations and discussions at the meeting.


Assuntos
Diagnóstico por Imagem/métodos , Infecções por HIV/prevenção & controle , Infecções por HIV/terapia , Vacinas contra a AIDS/imunologia , Síndrome da Imunodeficiência Adquirida , Animais , Congressos como Assunto , Diagnóstico por Imagem/instrumentação , HIV/imunologia , Humanos , National Institutes of Health (U.S.) , Síndrome de Imunodeficiência Adquirida dos Símios , Estados Unidos
4.
AIDS Res Hum Retroviruses ; 32(2): 109-19, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26670361

RESUMO

The number of humanized mouse models for the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) and other infectious diseases has expanded rapidly over the past 8 years. Highly immunodeficient mouse strains, such as NOD/SCID/gamma chain(null) (NSG, NOG), support better human hematopoietic cell engraftment. Another improvement is the derivation of highly immunodeficient mice, transgenic with human leukocyte antigens (HLAs) and cytokines that supported development of HLA-restricted human T cells and heightened human myeloid cell engraftment. Humanized mice are also used to study the HIV reservoir using new imaging techniques. Despite these advances, there are still limitations in HIV immune responses and deficits in lymphoid structures in these models in addition to xenogeneic graft-versus-host responses. To understand and disseminate the improvements and limitations of humanized mouse models to the scientific community, the NIH sponsored and convened a meeting on April 15, 2015 to discuss the state of knowledge concerning these questions and best practices for selecting a humanized mouse model for a particular scientific investigation. This report summarizes the findings of the NIH meeting.


Assuntos
Síndrome da Imunodeficiência Adquirida/imunologia , Doenças Transmissíveis/imunologia , Modelos Animais de Doenças , Síndrome da Imunodeficiência Adquirida/virologia , Animais , Doença Enxerto-Hospedeiro/imunologia , HIV-1/imunologia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , National Institute of Allergy and Infectious Diseases (U.S.) , Estados Unidos
5.
Virology ; 422(2): 402-12, 2012 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-22153299

RESUMO

Mouse monoclonal antibodies with varying specificities against the Gag capsid of simian and human immunodeficiency virus (SIV/HIV) were generated by immunizing mice with whole inactivated SIVagmTYO-1. Monoclonal antibody AG3.0 showed the broadest reactivity recognizing the Gag capsid protein (p24-27) and Gag precursors p38, p55, and p150 of HIV-1, HIV-2, SIVmac, and SIVagm. Using overlapping peptides, the AG3.0 epitope was mapped in capsid to a sequence (SPRTLNA) conserved among HIV-1, HIV-2, SIVrcm, SIVsm/mac, and SIVagm related viruses. Because of its broad cross-reactivity, AG3.0 was used to develop an antigen capture assay with a lower detection limit of 100 pg/ml HIV-1 Gag p24. Interestingly, AG3.0 was found to have a faster binding on/off rate for SIVagmVer and SIVmac Gag than for SIVagmSab Gag, possibly due to differences outside the SPRTLNA motif. In addition, the ribonucleic acid (RNA) coding for AG3.0 was sequenced to facilitate the development of humanized monoclonal antibodies.


Assuntos
Anticorpos Monoclonais/imunologia , Proteínas do Capsídeo/imunologia , HIV-1/imunologia , HIV-2/imunologia , Vírus da Imunodeficiência Símia/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/metabolismo , Linfócitos T CD4-Positivos , Linhagem Celular , Reações Cruzadas , Ensaio de Imunoadsorção Enzimática , Mapeamento de Epitopos , Humanos , Camundongos , Dados de Sequência Molecular
6.
Res Microbiol ; 162(10): 1006-10, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21907793

RESUMO

The vaginal microbiome, which harbors beneficial Lactobacillus strains, is believed to be a major host defense mechanism for preventing infections of the urogenital tract. It has been suggested that the gastrointestinal tract serves as a reservoir for lactobacilli that colonize the vagina. Using rhesus macaques, we examined whether oral delivery of human vaginal Lactobacillus jensenii 1153-1646, a GusA-producing strain, would result in colonization of the rectum and the vagina. Lactobacilli were identified from the vagina tracts of three macaques on the basis of ß-glucuronidase enzyme production, 16S rRNA gene sequence and DNA homology using a repetitive sequence-based polymerase chain reaction.


Assuntos
Glucuronidase/metabolismo , Lactobacillus/isolamento & purificação , Probióticos/administração & dosagem , Vagina/microbiologia , Administração Oral , Animais , Fezes/microbiologia , Feminino , Trato Gastrointestinal/microbiologia , Glucuronidase/genética , Humanos , Lactobacillus/classificação , Lactobacillus/enzimologia , Lactobacillus/genética , Macaca mulatta , Reação em Cadeia da Polimerase , Gravidez , RNA Ribossômico 16S/genética , Reto/microbiologia , Análise de Sequência de DNA
7.
J Virol ; 85(17): 8702-8, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21715501

RESUMO

Many species of African nonhuman primates are natural hosts for individual strains of simian immunodeficiency virus (SIV). These infected animals do not, however, develop AIDS. Here we show that multiple species of African nonhuman primate species characteristically have low frequencies of CD4(+) T cells and high frequencies of both T cells that express only the alpha-chain of CD8 and double-negative T cells. These subsets of T cells are capable of eliciting functions generally associated with CD4(+) T cells, yet these cells lack surface expression of the CD4 protein and are, therefore, poor targets for SIV in vivo. These data demonstrate that coevolution with SIV has, in several cases, involved downregulation of receptors for the virus by otherwise-susceptible host target cells. Understanding the genetic factors that lead to downregulation of these receptors may lead to therapeutic interventions that mimic this modulation in progressive infections.


Assuntos
Antígenos CD4/análise , Primatas/virologia , Vírus da Imunodeficiência Símia/crescimento & desenvolvimento , Vírus da Imunodeficiência Símia/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/virologia , Animais , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Subpopulações de Linfócitos T/química
8.
J Med Primatol ; 40(3): 200-4, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21401622

RESUMO

An SIV-infected rhesus macaque presented with anemia, hypercalcemia, and hyperglobulinemia. Neoplastic round cells with plasma cell morphology infiltrated multiple organs and stained immunohistochemically positive for CD45, MUM1/IRF4, CD138, VS38C, and Kappa light chain and variably positive for CD20 and CD79a, consistent with a B-cell neoplasm with plasma cell differentiation.


Assuntos
Diferenciação Celular , Hipergamaglobulinemia/veterinária , Leucemia Plasmocitária/veterinária , Macaca mulatta , Plasmócitos/patologia , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Vírus da Imunodeficiência Símia , Animais , Feminino , Hipergamaglobulinemia/complicações , Hipergamaglobulinemia/diagnóstico , Hipergamaglobulinemia/patologia , Leucemia Plasmocitária/complicações , Leucemia Plasmocitária/diagnóstico , Leucemia Plasmocitária/patologia , Ativação Linfocitária
9.
AIDS Res Ther ; 8(1): 3, 2011 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-21255437

RESUMO

BACKGROUND: In many preclinical AIDS research studies, antiretroviral therapy (ART) is administered to experimentally simian immunodeficiency (SIV)-infected rhesus macaques for reduction of viral load to undetectable levels. Prolonged treatment of macaques with a high dose of PMPA (9-[2-(r)-(phosphonomethoxy) propyl] adenine or tenofovir; 30 mg/kg of body weight subcutaneously once daily) can result in proximal renal tubular dysfunction, a Fanconi-like syndrome characterized by glucosuria, aminoaciduria, hypophosphatemia, and bone pathology. In contrast, chronic administration of a low dose of PMPA (10 mg/kg subcutaneously once daily) starting at birth does not seem to be associated with any adverse health effects within 3 years of treatment. In contrast to PMPA, limited information on systemic toxicity in rhesus monkeys is available for FTC (5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine; emtricitabine) and stavudine (d4T). RESULTS: In this study, the clinical and biochemical correlates of tubular nephrosis in SIV-infected rhesus macaques associated with systemic administration of high-dose ART consisting of the three nucleoside analog inhibitors PMPA, FTC, and d4T were investigated. It was found that acute renal failure was uncommon (7.1% of treated animals) and that morphologic evidence of nephropathy, which persisted for more than 300 days following discontinuation of the drug cocktail, was more frequent (52.4% of treated animals). While parameters from single time points lacked predictive value, biochemical alterations in Blood Urea Nitrogen (BUN) and phosphorus were frequently identified longitudinally in the blood of ART-treated animals that developed evidence of nephropathy, and these longitudinal changes correlated with disease severity. CONCLUSIONS: Recommendations are proposed to limit the impact of drug-induced renal disease in future SIV macaque studies.

10.
AIDS Res Ther ; 7: 22, 2010 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-20618951

RESUMO

BACKGROUND: At present, there is no effective vaccine or other approved product for the prevention of sexually transmitted human immunodeficiency virus type 1 (HIV-1) infection. It has been reported that women in resource-poor communities use vaginally applied citrus juices as topical microbicides. These easily accessible food products have historically been applied to prevent pregnancy and sexually transmitted diseases. The aim of this study was to evaluate the efficacy and cytotoxicity of these substances using an established topical microbicide testing algorithm. Freshly squeezed lemon and lime juice and household vinegar were tested in their original state or in pH neutralized form for efficacy and cytotoxicity in the CCR5-tropic cell-free entry and cell-associated transmission assays, CXCR4-tropic entry and fusion assays, and in a human PBMC-based anti-HIV-1 assay. These products were also tested for their effect on viability of cervico-vaginal cell lines, human cervical explant tissues, and beneficial Lactobacillus species. RESULTS: Natural lime and lemon juice and household vinegar demonstrated anti-HIV-1 activity and cytotoxicity in transformed cell lines. Neutralization of the products reduced both anti-HIV-1 activity and cytotoxicity, resulting in a low therapeutic window for both acidic and neutralized formulations. For the natural juices and vinegar, the IC50 was

11.
J Med Primatol ; 38(2): 125-36, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19367737

RESUMO

BACKGROUND: We sought to establish a nonhuman primate model of vaginal Lactobacillus colonization suitable for evaluating live microbial microbicide candidates. METHODS: Vaginal and rectal microflora in Chinese rhesus macaques (Macaca mulatta) were analyzed, with cultivable bacteria identified by 16S rRNA gene sequencing. Live lactobacilli were intravaginally administered to evaluate bacterial colonization. RESULTS: Chinese rhesus macaques harbored abundant vaginal Lactobacillus, with Lactobacillus johnsonii as the predominant species. Like humans, most examined macaques harbored only one vaginal Lactobacillus species. Vaginal and rectal Lactobacillus isolates from the same animal exhibited different genetic and biochemical profiles. Vaginal Lactobacillus was cleared by a vaginal suppository of azithromycin, and endogenous L. johnsonii was subsequently restored by intravaginal inoculation. Importantly, prolonged colonization of a human vaginal Lactobacillus jensenii was established in these animals. CONCLUSIONS: The Chinese rhesus macaque harbors vaginal Lactobacillus and is a potentially useful model to support the pre-clinical evaluation of Lactobacillus-based topical microbicides.


Assuntos
Lactobacillus/isolamento & purificação , Macaca mulatta , Modelos Animais , Vagina/microbiologia , Administração Intravaginal , Animais , Feminino , Humanos , Lactobacillus/genética , Lactobacillus/fisiologia , Probióticos/administração & dosagem , RNA Bacteriano/genética , RNA Ribossômico 16S/genética , Reto/microbiologia , Vaginite/prevenção & controle
13.
Nucleic Acids Res ; 37(Database issue): D417-22, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18927109

RESUMO

The 'Human Immunodeficiency Virus Type 1 (HIV-1), Human Protein Interaction Database', available through the National Library of Medicine at www.ncbi.nlm.nih.gov/RefSeq/HIVInteractions, was created to catalog all interactions between HIV-1 and human proteins published in the peer-reviewed literature. The database serves the scientific community exploring the discovery of novel HIV vaccine candidates and therapeutic targets. To facilitate this discovery approach, the following information for each HIV-1 human protein interaction is provided and can be retrieved without restriction by web-based downloads and ftp protocols: Reference Sequence (RefSeq) protein accession numbers, Entrez Gene identification numbers, brief descriptions of the interactions, searchable keywords for interactions and PubMed identification numbers (PMIDs) of journal articles describing the interactions. Currently, 2589 unique HIV-1 to human protein interactions and 5135 brief descriptions of the interactions, with a total of 14,312 PMID references to the original articles reporting the interactions, are stored in this growing database. In addition, all protein-protein interactions documented in the database are integrated into Entrez Gene records and listed in the 'HIV-1 protein interactions' section of Entrez Gene reports. The database is also tightly linked to other databases through Entrez Gene, enabling users to search for an abundance of information related to HIV pathogenesis and replication.


Assuntos
Bases de Dados de Proteínas , HIV-1/metabolismo , Mapeamento de Interação de Proteínas , Proteínas Virais/metabolismo , Síndrome da Imunodeficiência Adquirida/virologia , Gráficos por Computador , Humanos , Proteínas/metabolismo , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo
14.
AIDS Res Hum Retroviruses ; 24(12): 1497-502, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19025396

RESUMO

Although many interactions between HIV-1 and human proteins have been reported in the scientific literature, no publicly accessible source for efficiently reviewing this information was available. Therefore, a project was initiated in an attempt to catalogue all published interactions between HIV-1 and human proteins. HIV-related articles in PubMed were used to develop a database containing names, Entrez GeneIDs, and RefSeq protein accession numbers of interacting proteins. Furthermore, brief descriptions of the interactions, PubMed identification numbers of articles describing the interactions, and keywords for searching the interactions were incorporated. Over 100,000 articles were reviewed, resulting in the identification of 1448 human proteins that interact with HIV-1 comprising 2589 unique HIV-1-to-human protein interactions. Preliminary analysis of the extracted data indicates 32% were direct physical interactions (e.g., binding) and 68% were indirect interactions (e.g., upregulation through activation of signaling pathways). Interestingly, 37% of human proteins in the database were found to interact with more than one HIV-1 protein. For example, the signaling protein mitogen-activated protein kinase 1 has a surprising range of interactions with 10 different HIV-1 proteins. Moreover, large numbers of interactions were published for the HIV-1 regulatory protein Tat and envelope proteins: 30% and 33% of total interactions identified, respectively. The database is accessible at http://www.ncbi.nlm.nih.gov/RefSeq/HIVInteractions/ and is cross-linked to other National Center for Biotechnology Information databases and programs via Entrez Gene. This database represents a unique and continuously updated scientific resource for understanding HIV-1 replication and pathogenesis to assist in accelerating the development of effective therapeutic and vaccine interventions.


Assuntos
Bases de Dados de Proteínas , Infecções por HIV/virologia , HIV-1/fisiologia , Interações Hospedeiro-Patógeno , Proteínas Virais/metabolismo , Humanos , National Library of Medicine (U.S.) , Estados Unidos
15.
Proc Natl Acad Sci U S A ; 105(14): 5525-30, 2008 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-18378908

RESUMO

In the absence of an effective vaccine, there is an urgent need for safe and effective antiviral agents to prevent transmission of HIV. Here, we report that an amphipathic alpha-helical peptide derived from the hepatitis C virus NS5A anchor domain (designated C5A in this article) that has been shown to be virocidal for the hepatitis C virus (HCV) also has potent antiviral activity against HIV. C5A exhibits a broad range of antiviral activity against HIV isolates, and it prevents infection of the three in vivo targets of HIV: CD4(+) T lymphocytes, macrophages, and dendritic cells by disrupting the integrity of the viral membrane and capsid core while preserving the integrity of host membranes. C5A can interrupt an ongoing T cell infection, and it can prevent transmigration of HIV through primary genital epithelial cells, infection of mucosal target cells and transfer from dendritic cells to T cells ex vivo, justifying future experiments to determine whether C5A can prevent HIV transmission in vivo.


Assuntos
Infecções por HIV/prevenção & controle , HIV/efeitos dos fármacos , Hepacivirus/química , Fragmentos de Peptídeos/farmacologia , Proteínas não Estruturais Virais/farmacologia , Linfócitos T CD4-Positivos/virologia , Células Cultivadas , Células Dendríticas/virologia , Humanos , Macrófagos/virologia , Fragmentos de Peptídeos/uso terapêutico , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/uso terapêutico
16.
Antimicrob Agents Chemother ; 52(5): 1768-81, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18316528

RESUMO

Topical microbicides are self-administered, prophylactic products for protection against sexually transmitted pathogens. A large number of compounds with known anti-human immunodeficiency virus type 1 (HIV-1) inhibitory activity have been proposed as candidate topical microbicides. To identify potential leads, an in vitro screening algorithm was developed to evaluate candidate microbicides in assays that assess inhibition of cell-associated and cell-free HIV-1 transmission, entry, and fusion. The algorithm advances compounds by evaluation in a series of defined assays that generate measurements of relative antiviral potency to determine advancement or failure. Initial testing consists of a dual determination of inhibitory activity in the CD4-dependent CCR5-tropic cell-associated transmission inhibition assay and in the CD4/CCR5-mediated HIV-1 entry assay. The activity is confirmed by repeat testing, and identified actives are advanced to secondary screens to determine their effect on transmission of CXCR4-tropic viruses in the presence or absence of CD4 and their ability to inhibit CXCR4- and CCR5-tropic envelope-mediated cell-to-cell fusion. In addition, confirmed active compounds are also evaluated in the presence of human seminal plasma, in assays incorporating a pH 4 to 7 transition, and for growth inhibition of relevant strains of lactobacilli. Leads may then be advanced for specialized testing, including determinations in human cervical explants and in peripheral blood mononuclear cells against primary HIV subtypes, combination testing with other inhibitors, and additional cytotoxicity assays. PRO 2000 and SPL7013 (the active component of VivaGel), two microbicide products currently being evaluated in human clinical trials, were tested in this in vitro algorithm and were shown to be highly active against CCR5- and CXCR4-tropic HIV-1 infection.


Assuntos
Algoritmos , Fármacos Anti-HIV/farmacologia , Anti-Infecciosos Locais/farmacologia , HIV-1/efeitos dos fármacos , Amidas/farmacologia , Anilidas/farmacologia , Antagonistas dos Receptores CCR5 , Antígenos CD4/imunologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Furanos/farmacologia , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Naftalenossulfonatos/farmacologia , Polímeros/farmacologia , Compostos de Amônio Quaternário/farmacologia , Receptores CXCR4/antagonistas & inibidores , Tioamidas
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