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2.
Life Sci Alliance ; 3(8)2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32576602

RESUMEN

HIV and EBV are human pathogens that cause a considerable burden to worldwide health. In combination, these viruses are linked to AIDS-associated lymphomas. We found that EBV, which transforms B cells, renders them susceptible to HIV-1 infection in a CXCR4 and CD4-dependent manner in vitro and that CXCR4-tropic HIV-1 integrates into the genome of these B cells with the same molecular profile as in autologous CD4+ T cells. In addition, we established a humanized mouse model to investigate the in vivo interactions of EBV and HIV-1 upon coinfection. The respective mice that reconstitute human immune system components upon transplantation with CD34+ human hematopoietic progenitor cells could recapitulate aspects of EBV and HIV immunobiology observed in dual-infected patients. Upon coinfection of humanized mice, EBV/HIV dual-infected B cells could be detected, but were susceptible to CD8+ T-cell-mediated immune control.


Asunto(s)
Infecciones por VIH/inmunología , Infecciones por VIH/virología , Herpesvirus Humano 4/patogenicidad , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Linfocitos B/virología , Antígenos CD4/inmunología , Antígenos CD4/metabolismo , Coinfección , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/metabolismo , Susceptibilidad a Enfermedades/virología , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por VIH/genética , Seropositividad para VIH , VIH-1/metabolismo , VIH-1/patogenicidad , Células Madre Hematopoyéticas/patología , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Receptores CXCR4/metabolismo , Receptores CXCR4/fisiología , Linfocitos T/inmunología
3.
J Infect Dis ; 217(12): 1883-1888, 2018 05 25.
Artículo en Inglés | MEDLINE | ID: mdl-29528417

RESUMEN

Pegylated interferon-alpha (pIFN-α) is suggested to lower human immunodeficiency virus type-1 (HIV-1) DNA load in antiretroviral therapy (ART)-treated patients. We studied kinetics of HIV-1 DNA levels in 40 HIV-1/hepatitis C virus (HCV) coinfected patients, treated with pIFN-α for HCV and categorized into 3 groups according to start of ART: chronic HIV-1 infection (n = 22), acute HIV-1 infection (n = 8), no-ART (n = 10). Total HIV-1 DNA levels in 247 peripheral blood mononuclear cell samples were stable before, during, and after pIFN-α treatment in all groups. Our results question the benefit of pIFN-α as an immunotherapeutic agent for reducing the HIV-1 reservoir.


Asunto(s)
Coinfección/tratamiento farmacológico , ADN Viral/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Carga Viral/efectos de los fármacos , Adulto , Antivirales/uso terapéutico , Coinfección/virología , Femenino , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/virología , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/virología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
4.
Mol Cell Proteomics ; 16(4 suppl 1): S108-S123, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28223351

RESUMEN

Host-directed therapies against HIV-1 are thought to be critical for long term containment of the HIV-1 pandemic but remain elusive. Because HIV-1 infects and manipulates important effectors of both the innate and adaptive immune system, identifying modulations of the host cell systems in humans during HIV-1 infection may be crucial for the development of immune based therapies. Here, we quantified the changes of the proteome in human CD4+ T cells upon HIV-1 infection, both in vitro and in vivo A SWATH-MS approach was used to measure the proteome of human primary CD4+ T cells infected with HIV-1 in vitro as well as CD4+ T cells from HIV-1-infected patients with paired samples on and off antiretroviral treatment. In the in vitro experiment, the proteome of CD4+ T cells was quantified over a time course following HIV-1 infection. 1,725 host cell proteins and 4 HIV-1 proteins were quantified, with 145 proteins changing significantly during the time course. Changes in the proteome peaked 24 h after infection, concomitantly with significant HIV-1 protein production. In the in vivo branch of the study, CD4+ T cells from viremic patients and those with no detectable viral load after treatment were sorted, and the proteomes were quantified. We consistently detected 895 proteins, 172 of which were considered to be significantly different between the viremic patients and patients undergoing successful treatment. The proteome of the in vitro-infected CD4+ T cells was modulated on multiple functional levels, including TLR-4 signaling and the type 1 interferon signaling pathway. Perturbations in the type 1 interferon signaling pathway were recapitulated in CD4+ T cells from patients. The study shows that proteome maps generated by SWATH-MS indicate a range of functionally significant changes in the proteome of HIV-infected human CD4+ T cells. Exploring these perturbations in more detail may help identify new targets for immune based interventions.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Infecciones por VIH/inmunología , VIH-1/fisiología , Proteoma/metabolismo , Proteómica/métodos , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/virología , Células Cultivadas , Regulación de la Expresión Génica , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Interacciones Huésped-Patógeno , Humanos , Espectrometría de Masas/métodos , Mapas de Interacción de Proteínas , Carga Viral/efectos de los fármacos , Replicación Viral/efectos de los fármacos
5.
J Virol ; 88(14): 7738-52, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24760893

RESUMEN

Myxovirus resistance 2 (Mx2/MxB) has recently been uncovered as an effector of the anti-HIV-1 activity of type I interferons (IFNs) that inhibits HIV-1 at an early stage postinfection, after reverse transcription but prior to proviral integration into host DNA. The mechanistic details of Mx2 antiviral activity are not yet understood, but a few substitutions in the HIV-1 capsid have been shown to confer resistance to Mx2. Through a combination of in vitro evolution and unbiased mutagenesis, we further map the determinants of sensitivity to Mx2 and reveal that multiple capsid (CA) surfaces define sensitivity to Mx2. Intriguingly, we reveal an unanticipated sensitivity determinant within the C-terminal domain of capsid. We also report that Mx2s derived from multiple primate species share the capacity to potently inhibit HIV-1, whereas selected nonprimate orthologs have no such activity. Like TRIM5α, another CA targeting antiretroviral protein, primate Mx2s exhibit species-dependent variation in antiviral specificity against at least one extant virus and multiple HIV-1 capsid mutants. Using a combination of chimeric Mx2 proteins and evolution-guided approaches, we reveal that a single residue close to the N terminus that has evolved under positive selection can determine antiviral specificity. Thus, the variable N-terminal region can define the spectrum of viruses inhibited by Mx2. Importance: Type I interferons (IFNs) inhibit the replication of most mammalian viruses. IFN stimulation upregulates hundreds of different IFN-stimulated genes (ISGs), but it is often unclear which ISGs are responsible for inhibition of a given virus. Recently, Mx2 was identified as an ISG that contributes to the inhibition of HIV-1 replication by type I IFN. Thus, Mx2 might inhibit HIV-1 replication in patients, and this inhibitory action might have therapeutic potential. The mechanistic details of how Mx2 inhibits HIV-1 are currently unclear, but the HIV-1 capsid protein is the likely viral target. Here, we determine the regions of capsid that specify sensitivity to Mx2. We demonstrate that Mx2 from multiple primates can inhibit HIV-1, whereas Mx2 from other mammals (dogs and sheep) cannot. We also show that primate variants of Mx2 differ in the spectrum of lentiviruses they inhibit and that a single residue in Mx2 can determine this antiviral specificity.


Asunto(s)
Proteína p24 del Núcleo del VIH/inmunología , VIH-1/inmunología , Proteínas de Resistencia a Mixovirus/inmunología , Animales , Análisis Mutacional de ADN , Evolución Molecular , Proteína p24 del Núcleo del VIH/genética , VIH-1/genética , Humanos , Mutagénesis
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