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1.
Annu Rev Immunol ; 34: 575-608, 2016 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-27168245

RESUMEN

Mucosal surfaces provide a remarkably effective barrier against potentially dangerous pathogens. Therefore, enhancing mucosal immunity through vaccines-strengthening that first line of defense-holds significant promise for reducing the burden of viral diseases. The large and varied class of viral pathogens, however, continues to present thorny challenges to vaccine development. Two primary difficulties exist: Viruses exhibit a stunning diversity of strategies for evading the host immune response, and even when we understand the nature of effective immune protection against a given virus, eliciting that protection is technically challenging. Only a few mucosal vaccines have surmounted these obstacles thus far. Recent developments, however, could greatly improve vaccine design. In this review, we first sketch out our understanding of mucosal immunity and then compare the herpes simplex virus, human immunodeficiency virus, and influenza virus to illustrate the distinct challenges of developing successful vaccines and to outline potential solutions.


Asunto(s)
VIH/inmunología , Evasión Inmune , Inmunidad Mucosa , Orthomyxoviridae/inmunología , Simplexvirus/inmunología , Vacunas Virales/inmunología , Virosis/inmunología , Animales , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/metabolismo , Humanos , Memoria Inmunológica , Virosis/prevención & control
2.
Annu Rev Immunol ; 34: 635-59, 2016 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-27168247

RESUMEN

HIV employs multiple means to evade the humoral immune response, particularly the elicitation of and recognition by broadly neutralizing antibodies (bnAbs). Such antibodies can act antivirally against a wide spectrum of viruses by targeting relatively conserved regions on the surface HIV envelope trimer spike. Elicitation of and recognition by bnAbs are hindered by the arrangement of spikes on virions and the relatively difficult access to bnAb epitopes on spikes, including the proximity of variable regions and a high density of glycans. Yet, in a small proportion of HIV-infected individuals, potent bnAb responses do develop, and isolation of the corresponding monoclonal antibodies has been facilitated by identification of favorable donors with potent bnAb sera and by development of improved methods for human antibody generation. Molecular studies of recombinant Env trimers, alone and in interaction with bnAbs, are providing new insights that are fueling the development and testing of promising immunogens aimed at the elicitation of bnAbs.


Asunto(s)
Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Anti-VIH/metabolismo , Infecciones por VIH/inmunología , VIH/inmunología , Inmunización Pasiva/métodos , Virión/inmunología , Animales , Secuencia Conservada , Infecciones por VIH/prevención & control , Humanos , Evasión Inmune , Inmunización Pasiva/tendencias , Proteínas del Envoltorio Viral/inmunología
3.
Immunity ; 53(5): 908-924, 2020 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-33207216

RESUMEN

Understanding the earliest immune responses following HIV infection is critical to inform future vaccines and therapeutics. Here, we review recent prospective human studies in at-risk populations that have provided insight into immune responses during acute infection, including additional relevant data from non-human primate (NHP) studies. We discuss the timing, nature, and function of the diverse immune responses induced, the onset of immune dysfunction, and the effects of early anti-retroviral therapy administration. Treatment at onset of viremia mitigates peripheral T and B cell dysfunction, limits seroconversion, and enhances cellular antiviral immunity despite persistence of infection in lymphoid tissues. We highlight pertinent areas for future investigation, and how application of high-throughput technologies, alongside targeted NHP studies, may elucidate immune response features to target in novel preventions and cures.


Asunto(s)
Evolución Biológica , Infecciones por VIH/inmunología , VIH/inmunología , Interacciones Huésped-Patógeno/inmunología , Inmunidad , Enfermedad Aguda , Inmunidad Adaptativa , Animales , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Manejo de la Enfermedad , Infecciones por VIH/terapia , Infecciones por VIH/virología , Humanos , Inmunidad Innata , Mediadores de Inflamación/metabolismo , Tejido Linfoide/inmunología , Tejido Linfoide/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/inmunología , Tiempo de Tratamiento , Resultado del Tratamiento , Carga Viral
4.
Nat Immunol ; 17(10): 1187-96, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27487330

RESUMEN

During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell-derived malignancies.


Asunto(s)
Infecciones por Arenaviridae/inmunología , Linfocitos B/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , VIH/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diferenciación Celular , Células Cultivadas , Regulación de la Expresión Génica , Centro Germinal/patología , Centro Germinal/virología , Factor Nuclear 1-alfa del Hepatocito/genética , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
5.
Nat Immunol ; 17(5): 593-603, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26950238

RESUMEN

Persistent viral infections are characterized by the simultaneous presence of chronic inflammation and T cell dysfunction. In prototypic models of chronicity--infection with human immunodeficiency virus (HIV) or lymphocytic choriomeningitis virus (LCMV)--we used transcriptome-based modeling to reveal that CD4(+) T cells were co-exposed not only to multiple inhibitory signals but also to tumor-necrosis factor (TNF). Blockade of TNF during chronic infection with LCMV abrogated the inhibitory gene-expression signature in CD4(+) T cells, including reduced expression of the inhibitory receptor PD-1, and reconstituted virus-specific immunity, which led to control of infection. Preventing signaling via the TNF receptor selectively in T cells sufficed to induce these effects. Targeted immunological interventions to disrupt the TNF-mediated link between chronic inflammation and T cell dysfunction might therefore lead to therapies to overcome persistent viral infection.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Adolescente , Adulto , Anciano , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Citometría de Flujo , Células HEK293 , VIH/fisiología , Infecciones por VIH/genética , Infecciones por VIH/virología , Interacciones Huésped-Patógeno/inmunología , Humanos , Immunoblotting , Coriomeningitis Linfocítica/genética , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Receptores del Factor de Necrosis Tumoral/genética , Receptores del Factor de Necrosis Tumoral/inmunología , Receptores del Factor de Necrosis Tumoral/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transcriptoma/efectos de los fármacos , Transcriptoma/genética , Transcriptoma/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Adulto Joven
6.
Physiol Rev ; 100(2): 603-632, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-31600121

RESUMEN

Despite anti-retroviral therapy (ART), human immunodeficiency virus-1 (HIV)-related pulmonary disease continues to be a major cause of morbidity and mortality for people living with HIV (PLWH). The spectrum of lung diseases has changed from acute opportunistic infections resulting in death to chronic lung diseases for those with access to ART. Chronic immune activation and suppression can result in impairment of innate immunity and progressive loss of T cell and B cell functionality with aberrant cytokine and chemokine responses systemically as well as in the lung. HIV can be detected in the lungs of PLWH and has profound effects on cellular immune functions. In addition, HIV-related lung injury and disease can occur secondary to a number of mechanisms including altered pulmonary and systemic inflammatory pathways, viral persistence in the lung, oxidative stress with additive effects of smoke exposure, microbial translocation, and alterations in the lung and gut microbiome. Although ART has had profound effects on systemic viral suppression in HIV, the impact of ART on lung immunology still needs to be fully elucidated. Understanding of the mechanisms by which HIV-related lung diseases continue to occur is critical to the development of new preventive and therapeutic strategies to improve lung health in PLWH.


Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/inmunología , Asma/inmunología , Infecciones por VIH/inmunología , VIH/inmunología , Hipertensión Pulmonar/inmunología , Neoplasias Pulmonares/inmunología , Pulmón/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Infecciones del Sistema Respiratorio/inmunología , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Infecciones Oportunistas Relacionadas con el SIDA/microbiología , Infecciones Oportunistas Relacionadas con el SIDA/virología , Animales , Fármacos Anti-VIH/uso terapéutico , Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Asma/virología , Modelos Animales de Enfermedad , VIH/efectos de los fármacos , VIH/patogenicidad , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Interacciones Huésped-Patógeno , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/virología , Huésped Inmunocomprometido , Pulmón/efectos de los fármacos , Pulmón/microbiología , Pulmón/virología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/virología , Pronóstico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/virología , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/virología , Factores de Riesgo
7.
Mol Cell ; 71(4): 637-648.e5, 2018 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-30118682

RESUMEN

Although macrophages are armed with potent antibacterial functions, Mycobacterium tuberculosis (Mtb) replicates inside these innate immune cells. Determinants of macrophage intrinsic bacterial control, and the Mtb strategies to overcome them, are poorly understood. To further study these processes, we used an affinity tag purification mass spectrometry (AP-MS) approach to identify 187 Mtb-human protein-protein interactions (PPIs) involving 34 secreted Mtb proteins. This interaction map revealed two factors involved in Mtb pathogenesis-the secreted Mtb protein, LpqN, and its binding partner, the human ubiquitin ligase CBL. We discovered that an lpqN Mtb mutant is attenuated in macrophages, but growth is restored when CBL is removed. Conversely, Cbl-/- macrophages are resistant to viral infection, indicating that CBL regulates cell-intrinsic polarization between antibacterial and antiviral immunity. Collectively, these findings illustrate the utility of this Mtb-human PPI map for developing a deeper understanding of the intricate interactions between Mtb and its host.


Asunto(s)
Proteínas Bacterianas/genética , VIH/genética , Interacciones Huésped-Patógeno , Mycobacterium tuberculosis/genética , Proteínas Proto-Oncogénicas c-cbl/genética , Factores de Virulencia/genética , Animales , Proteínas Bacterianas/inmunología , Línea Celular Tumoral , Chlamydia trachomatis/genética , Chlamydia trachomatis/inmunología , Regulación de la Expresión Génica , VIH/inmunología , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/inmunología , Humanos , Linfocitos/microbiología , Linfocitos/virología , Macrófagos/microbiología , Macrófagos/virología , Ratones , Mycobacterium tuberculosis/inmunología , Cultivo Primario de Células , Unión Proteica , Mapeo de Interacción de Proteínas , Proteínas Proto-Oncogénicas c-cbl/deficiencia , Proteínas Proto-Oncogénicas c-cbl/inmunología , Células RAW 264.7 , Transducción de Señal , Factores de Virulencia/inmunología
8.
Nat Immunol ; 14(11): 1104-7, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24145780

RESUMEN

As a result of decades of research-driven breakthroughs in basic and clinical science and recent advances in the broad-scale implementation of interventions for the prevention and treatment of infection with HIV, a turning point has been reached in the global HIV-AIDS pandemic. To end the pandemic and achieve the goal of an AIDS-free generation, researchers and clinicians must follow the dual pathway of optimizing the implementation of existing prevention and treatment interventions and discovering with basic and clinical research new and effective tools in both of these arenas.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/epidemiología , Síndrome de Inmunodeficiencia Adquirida/prevención & control , VIH/inmunología , Pandemias , Vacunas contra el SIDA/inmunología , Síndrome de Inmunodeficiencia Adquirida/inmunología , Síndrome de Inmunodeficiencia Adquirida/virología , Fármacos Anti-VIH/uso terapéutico , Anticuerpos Neutralizantes/inmunología , Antígenos Virales/inmunología , Terapia Antirretroviral Altamente Activa , Humanos , Estados Unidos/epidemiología
9.
Nat Immunol ; 14(1): 1-5, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23238748

RESUMEN

Antibody gene transfer, which involves the delivery of genes that encode potent, broadly neutralizing antibodies to human immunodeficiency virus (HIV), is a promising new strategy for preventing HIV infection. A satellite symposium at the AIDS Vaccine 2012 conference brought together many of the groups working in this field.


Asunto(s)
Vacunas contra el SIDA/genética , Anticuerpos Neutralizantes/genética , Anticuerpos Antivirales/genética , Técnicas de Transferencia de Gen , Infecciones por VIH/prevención & control , VIH/inmunología , Animales , Inmunoadhesinas CD4/genética , Inmunoadhesinas CD4/inmunología , Ensayos Clínicos como Asunto , Dependovirus , Modelos Animales de Enfermedad , Ingeniería Genética , Vectores Genéticos/genética , Humanos , Células Musculares/inmunología , Estados Unidos
10.
J Virol ; 97(11): e0109423, 2023 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-37874153

RESUMEN

IMPORTANCE: Despite the advent of highly active anti-retroviral therapy, people are still dying from HIV-related causes, many of whom are children, and a protective vaccine or cure is needed to end the HIV pandemic. Understanding the nature and activation states of immune cell subsets during infection will provide insights into the immunologic milieu associated with viremia suppression that can be harnessed via therapeutic strategies to achieve a functional cure, but these are understudied in pediatric subjects. We evaluated humoral and adaptive host immunity associated with suppression of viremia in rhesus macaques infected soon after birth with a pathogenic SHIV. The results from our study provide insights into the immune cell subsets and functions associated with viremia control in young macaques that may translate to pediatric subjects for the design of future anti-viral strategies in HIV-1-infected infants and children and contribute to an understudied area of HIV-1 pathogenesis in pediatric subjects.


Asunto(s)
Animales Recién Nacidos , Modelos Animales de Enfermedad , Infecciones por VIH , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio , Viremia , Animales , Niño , Humanos , Animales Recién Nacidos/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Macaca mulatta/inmunología , Macaca mulatta/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/inmunología , Virus de la Inmunodeficiencia de los Simios/fisiología , Viremia/inmunología , Viremia/virología , VIH/inmunología , VIH/fisiología
11.
PLoS Pathog ; 17(4): e1009522, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33872331

RESUMEN

Although HIV infection inhibits interferon responses in its target cells in vitro, interferon signatures can be detected in vivo soon after sexual transmission, mainly attributed to plasmacytoid dendritic cells (pDCs). In this study, we examined the physiological contributions of pDCs to early HIV acquisition using coculture models of pDCs with myeloid DCs, macrophages and the resting central, transitional and effector memory CD4 T cell subsets. pDCs impacted infection in a cell-specific manner. In myeloid cells, HIV infection was decreased via antiviral effects, cell maturation and downregulation of CCR5 expression. In contrast, in resting memory CD4 T cells, pDCs induced a subset-specific increase in intracellular HIV p24 protein expression without any activation or increase in CCR5 expression, as measured by flow cytometry. This increase was due to reactivation rather than enhanced viral spread, as blocking HIV entry via CCR5 did not alter the increased intracellular p24 expression. Furthermore, the load and proportion of cells expressing HIV DNA were restricted in the presence of pDCs while reverse transcriptase and p24 ELISA assays showed no increase in particle associated reverse transcriptase or extracellular p24 production. In addition, pDCs also markedly induced the expression of CD69 on infected CD4 T cells and other markers of CD4 T cell tissue retention. These phenotypic changes showed marked parallels with resident memory CD4 T cells isolated from anogenital tissue using enzymatic digestion. Production of IFNα by pDCs was the main driving factor for all these results. Thus, pDCs may reduce HIV spread during initial mucosal acquisition by inhibiting replication in myeloid cells while reactivating latent virus in resting memory CD4 T cells and retaining them for immune clearance.


Asunto(s)
Células Dendríticas/virología , Infecciones por VIH/virología , VIH/inmunología , Interferón-alfa/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Células Dendríticas/inmunología , Citometría de Flujo , VIH/genética , VIH/fisiología , Proteína p24 del Núcleo del VIH/genética , Proteína p24 del Núcleo del VIH/metabolismo , Infecciones por VIH/inmunología , Humanos , Células Mieloides/inmunología , Células Mieloides/virología , Fenotipo
12.
Nat Immunol ; 12(10): 925-7, 2011 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-21934670

RESUMEN

The antiviral factor APOBEC3G upregulates the expression of ligands for the activating receptor NKG2D via DNA damage induced by the viral protein Vpr in cells infected with human immunodeficiency virus. The virus overcomes greater susceptibility to natural killer cell­mediated lysis by targeting APOBEC3G for degradation.


Asunto(s)
Citidina Desaminasa/fisiología , VIH/inmunología , Células Asesinas Naturales/inmunología , Linfocitos T/virología , Desaminasa APOBEC-3G , Humanos
13.
Nat Immunol ; 12(10): 975-83, 2011 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-21874023

RESUMEN

APOBEC3G (A3G) is an intrinsic antiviral factor that inhibits the replication of human immunodeficiency virus (HIV) by deaminating cytidine residues to uridine. This causes guanosine-to-adenosine hypermutation in the opposite strand and results in inactivation of the virus. HIV counteracts A3G through the activity of viral infectivity factor (Vif), which promotes degradation of A3G. We report that viral protein R (Vpr), which interacts with a uracil glycosylase, also counteracted A3G by diminishing the incorporation of uridine. However, this process resulted in activation of the DNA-damage-response pathway and the expression of natural killer (NK) cell-activating ligands. Our results show that pathogen-induced deamination of cytidine and the DNA-damage response to virus-mediated repair of the incorporation of uridine enhance the recognition of HIV-infected cells by NK cells.


Asunto(s)
Citidina Desaminasa/fisiología , VIH/inmunología , Células Asesinas Naturales/inmunología , Linfocitos T/virología , Desaminasa APOBEC-3G , Células Cultivadas , Citotoxicidad Inmunológica , Daño del ADN , Productos del Gen vpr/fisiología , Humanos , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Uridina/metabolismo
14.
J Immunol ; 206(6): 1284-1296, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33568400

RESUMEN

Neutralizing Abs suppress HIV infection by accelerating viral clearance from blood circulation in addition to neutralization. The elimination mechanism is largely unknown. We determined that human liver sinusoidal endothelial cells (LSEC) express FcγRIIb as the lone Fcγ receptor, and using humanized FcγRIIb mouse, we found that Ab-opsonized HIV pseudoviruses were cleared considerably faster from circulation than HIV by LSEC FcγRIIb. Compared with humanized FcγRIIb-expressing mice, HIV clearance was significantly slower in FcγRIIb knockout mice. Interestingly, a pentamix of neutralizing Abs cleared HIV faster compared with hyperimmune anti-HIV Ig (HIVIG), although the HIV Ab/Ag ratio was higher in immune complexes made of HIVIG and HIV than pentamix and HIV. The effector mechanism of LSEC FcγRIIb was identified to be endocytosis. Once endocytosed, both Ab-opsonized HIV pseudoviruses and HIV localized to lysosomes. This suggests that clearance of HIV, endocytosis, and lysosomal trafficking within LSEC occur sequentially and that the clearance rate may influence downstream events. Most importantly, we have identified LSEC FcγRIIb-mediated endocytosis to be the Fc effector mechanism to eliminate cell-free HIV by Abs, which could inform development of HIV vaccine and Ab therapy.


Asunto(s)
Anticuerpos Neutralizantes/metabolismo , Endocitosis/inmunología , Células Endoteliales/inmunología , Infecciones por VIH/inmunología , Receptores de IgG/metabolismo , Animales , Capilares/citología , Capilares/inmunología , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Células Endoteliales/virología , Endotelio Vascular/citología , Endotelio Vascular/inmunología , Endotelio Vascular/metabolismo , Células HEK293 , VIH/inmunología , Infecciones por VIH/sangre , Infecciones por VIH/patología , Infecciones por VIH/virología , Voluntarios Sanos , Humanos , Hígado/irrigación sanguínea , Hígado/inmunología , Lisosomas/metabolismo , Lisosomas/virología , Masculino , Ratones , Ratones Noqueados , Cultivo Primario de Células , Receptores de IgG/genética
15.
Nature ; 548(7665): 108-111, 2017 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-28726771

RESUMEN

No immunogen to date has reliably elicited broadly neutralizing antibodies to HIV in humans or animal models. Advances in the design of immunogens that antigenically mimic the HIV envelope glycoprotein (Env), such as the soluble cleaved trimer BG505 SOSIP, have improved the elicitation of potent isolate-specific antibody responses in rabbits and macaques, but so far failed to induce broadly neutralizing antibodies. One possible reason for this failure is that the relevant antibody repertoires are poorly suited to target the conserved epitope regions on Env, which are somewhat occluded relative to the exposed variable epitopes. Here, to test this hypothesis, we immunized four cows with BG505 SOSIP. The antibody repertoire of cows contains long third heavy chain complementary determining regions (HCDR3) with an ultralong subset that can reach more than 70 amino acids in length. Remarkably, BG505 SOSIP immunization resulted in rapid elicitation of broad and potent serum antibody responses in all four cows. Longitudinal serum analysis for one cow showed the development of neutralization breadth (20%, n = 117 cross-clade isolates) in 42 days and 96% breadth (n = 117) at 381 days. A monoclonal antibody isolated from this cow harboured an ultralong HCDR3 of 60 amino acids and neutralized 72% of cross-clade isolates (n = 117) with a potent median IC50 of 0.028 µg ml-1. Breadth was elicited with a single trimer immunogen and did not require additional envelope diversity. Immunization of cows may provide an avenue to rapidly generate antibody prophylactics and therapeutics to address disease agents that have evolved to avoid human antibody responses.


Asunto(s)
Anticuerpos Neutralizantes/biosíntesis , Anticuerpos Neutralizantes/aislamiento & purificación , Bovinos/inmunología , VIH/inmunología , Inmunización , Secuencia de Aminoácidos , Animales , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/inmunología , Células HEK293 , Proteínas gp160 de Envoltorio del VIH/inmunología , Humanos
16.
Nature ; 543(7646): 559-563, 2017 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-28289286

RESUMEN

Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans. In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant long-term infection control. Animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of two potent passively transferred bNAbs (3BNC117 and 10-1074 (refs 13, 14)). Viraemia remained undetectable for 56-177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. Four additional animals maintained their counts of T cells carrying the CD4 antigen (CD4+) and very low levels of viraemia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4+ T cells in the six controller macaques. Infusion of a T-cell-depleting anti-CD8ß monoclonal antibody to the controller animals led to a specific decline in levels of CD8+ T cells and the rapid reappearance of plasma viraemia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy, beginning on day 3 after infection, experienced sustained rebound plasma viraemia when treatment was interrupted. Our results show that passive immunotherapy during acute SHIV infection differs from combination anti-retroviral therapy in that it facilitates the emergence of potent CD8+ T-cell immunity able to durably suppress virus replication.


Asunto(s)
Infecciones por VIH/inmunología , Infecciones por VIH/terapia , VIH/inmunología , Inmunización Pasiva , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/terapia , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/uso terapéutico , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Terapia Combinada , Modelos Animales de Enfermedad , Femenino , VIH/efectos de los fármacos , VIH/aislamiento & purificación , Anticuerpos Anti-VIH/administración & dosificación , Anticuerpos Anti-VIH/inmunología , Anticuerpos Anti-VIH/uso terapéutico , Infecciones por VIH/virología , Semivida , Macaca mulatta , Masculino , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Carga Viral/efectos de los fármacos , Carga Viral/inmunología , Viremia/inmunología , Viremia/terapia , Replicación Viral/efectos de los fármacos , Replicación Viral/inmunología
17.
PLoS Pathog ; 16(10): e1008869, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33002093

RESUMEN

People with HIV (PWH) are at increased risk for atherosclerotic cardiovascular disease (ASCVD). Proportions of vascular homing monocytes are enriched in PWH; however, little is known regarding monocyte-derived macrophages (MDMs) that may drive atherosclerosis in this population. We isolated PBMCs from people with and without HIV, and cultured these cells for 5 days in medium containing autologous serum to generate MDMs. Differential gene expression (DGE) analysis of MDMs from PWH identified broad alterations in innate immune signaling (IL-1ß, TLR expression, PPAR ßδ) and lipid processing (LXR/RXR, ACPP, SREBP1). Transcriptional changes aligned with the functional capabilities of these cells. Expression of activation markers and innate immune receptors (CD163, TLR4, and CD300e) was altered on MDMs from PWH, and these cells produced more TNFα, reactive oxygen species (ROS), and matrix metalloproteinases (MMPs) than did cells from people without HIV. MDMs from PWH also had greater lipid accumulation and uptake of oxidized LDL. PWH had increased serum levels of free fatty acids (FFAs) and ceramides, with enrichment of saturated FAs and a reduction in polyunsaturated FAs. Levels of lipid classes and species that are associated with CVD correlated with unique DGE signatures and altered metabolic pathway activation in MDMs from PWH. Here, we show that MDMs from PWH display a pro-atherogenic phenotype; they readily form foam cells, have altered transcriptional profiles, and produce mediators that likely contribute to accelerated ASCVD.


Asunto(s)
Aterosclerosis/etiología , Infecciones por VIH/virología , VIH/inmunología , Lípidos/sangre , Macrófagos/patología , Modelos Cardiovasculares , Monocitos/virología , Aterosclerosis/patología , Estudios de Casos y Controles , VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/virología , Monocitos/metabolismo , Transcriptoma
19.
J Med Virol ; 94(2): 791-794, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34647636

RESUMEN

We documented the outcome of an over 10-year (2011-2021) effort to diagnose acute and early HIV infections (AEHI) in an Infectious Diseases Outpatient Clinic with limited resources. Of a total of 132, 119 HIV-RNA tests were performed from 2017 to 2020, 12 cases were identified, using a simple algorithm: risk exposure of 6 weeks or less before the visit and/or symptoms compatible with acute retroviral syndrome 7-30 days after exposure and/or undetermined 3rd generation rapid diagnostic test or serology. AEHI diagnoses varied from 2.4% among asymptomatic to 25% for undetermined serology cases using this simple screening applicable to different settings.


Asunto(s)
Anticuerpos Anti-VIH/sangre , Infecciones por VIH/diagnóstico , Prueba de VIH/métodos , VIH/inmunología , ARN Viral/sangre , Enfermedad Aguda , Algoritmos , Brasil , Países en Desarrollo , Diagnóstico Precoz , Femenino , Humanos , Masculino , Factores de Tiempo , Carga Viral
20.
Immunity ; 39(4): 633-45, 2013 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-24138880

RESUMEN

Combination antiretroviral therapy for HIV infection improves immune function and eliminates the risk of AIDS-related complications but does not restore full health. HIV-infected adults have excess risk of cardiovascular, liver, kidney, bone, and neurologic diseases. Many markers of inflammation are elevated in HIV disease and strongly predictive of the risk of morbidity and mortality. A conceptual model has emerged to explain this syndrome of diseases where HIV-mediated destruction of gut mucosa leads to local and systemic inflammation. Translocated microbial products then pass through the liver, contributing to hepatic damage, impaired microbial clearance, and impaired protein synthesis. Chronic activation of monocytes and altered liver protein synthesis subsequently contribute to a hypercoagulable state. The combined effect of systemic inflammation and excess clotting on tissue function leads to end-organ disease. Multiple therapeutic interventions designed to reverse these pathways are now being tested in the clinic. It is likely that knowledge gained on how inflammation affects health in HIV disease could have implications for our understanding of other chronic inflammatory diseases and the biology of aging.


Asunto(s)
Infecciones por VIH/inmunología , VIH/inmunología , Mucosa Intestinal/inmunología , Trombofilia/inmunología , Factores de Edad , Fármacos Anti-VIH/uso terapéutico , Antiinflamatorios/uso terapéutico , Enfermedad Crónica , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/fisiopatología , Humanos , Inmunidad Innata , Inflamación/etiología , Inflamación/inmunología , Inflamación/fisiopatología , Mucosa Intestinal/fisiopatología , Hígado/inmunología , Hígado/fisiopatología , Modelos Inmunológicos , Monocitos/inmunología , Monocitos/patología , Insuficiencia Multiorgánica/etiología , Insuficiencia Multiorgánica/inmunología , Insuficiencia Multiorgánica/fisiopatología , Biosíntesis de Proteínas/inmunología , Trombofilia/tratamiento farmacológico , Trombofilia/etiología , Trombofilia/fisiopatología
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