RESUMEN
BK polyomavirus (BKV) frequently causes nephropathy (BKVN) in kidney transplant recipients (KTRs). BKV has also been implicated in the etiology of bladder and kidney cancers. We characterized BKV variants from two KTRs who developed BKVN followed by renal carcinoma. Both patients showed a swarm of BKV sequence variants encoding non-silent mutations in surface loops of the viral major capsid protein. The temporal appearance and disappearance of these mutations highlights the intra-patient evolution of BKV. Some of the observed mutations conferred resistance to antibody-mediated neutralization. The mutations also modified the spectrum of receptor glycans engaged by BKV during host cell entry. Intriguingly, all observed mutations were consistent with DNA damage caused by antiviral APOBEC3 cytosine deaminases. Moreover, APOBEC3 expression was evident upon immunohistochemical analysis of renal biopsies from KTRs. These results provide a snapshot of in-host BKV evolution and suggest that APOBEC3 may drive BKV mutagenesis in vivo.
Asunto(s)
Virus BK/genética , Citosina Desaminasa/fisiología , Trasplante de Riñón , Infecciones por Polyomavirus/virología , Infecciones Tumorales por Virus/virología , Desaminasas APOBEC , Adulto , Sustitución de Aminoácidos , Animales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Virus BK/inmunología , Proteínas de la Cápside/genética , Línea Celular , Mapeo Cromosómico , Citidina Desaminasa , Daño del ADN , ADN Viral/análisis , ADN Viral/genética , Femenino , Células HEK293 , Humanos , Italia , Enfermedades Renales/patología , Enfermedades Renales/virología , Masculino , Persona de Mediana Edad , Mutación , Infecciones por Polyomavirus/sangre , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/patología , Infecciones Tumorales por Virus/sangre , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/patologíaAsunto(s)
Núcleo Celular/virología , División del ADN , ADN Circular/metabolismo , ADN Viral/metabolismo , Virus de la Hepatitis B/genética , Desaminasas APOBEC , Antivirales/farmacología , Núcleo Celular/efectos de los fármacos , Núcleo Celular/genética , Citidina Desaminasa , Citocinas/farmacología , Citosina Desaminasa/fisiología , División del ADN/efectos de los fármacos , Daño del ADN/efectos de los fármacos , ADN Circular/efectos de los fármacos , ADN Viral/efectos de los fármacos , Virus de la Hepatitis B/efectos de los fármacos , HumanosRESUMEN
The RIG-I signaling pathway is critical in the activation of the type I IFN-dependent antiviral innate-immune response. We thus examined whether RIG-I activation can inhibit HIV replication in macrophages. We showed that the stimulation of monocyte-derived macrophages with 5'ppp-dsRNA, a synthetic ligand for RIG-I, induced the expression of RIG-I, IFN-α/ß, and several IRFs, key regulators of the IFN signaling pathway. In addition, RIG-I activation induced the expression of multiple intracellular HIV-restriction factors, including ISGs, several members of the APOBEC3 family, tetherin and CC chemokines, the ligands for HIV entry coreceptor (CCR5). The inductions of these factors were associated with the inhibition of HIV replication in macrophages stimulated by 5'ppp-dsRNA. These observations highlight the importance of RIG-I signaling in macrophage innate immunity against HIV, which can be beneficial for the treatment of HIV disease, where intracellular immune defense is compromised by the virus.
Asunto(s)
ARN Helicasas DEAD-box/fisiología , VIH-1/fisiología , Macrófagos/virología , Replicación Viral , Desaminasas APOBEC , Antígenos CD/fisiología , Células Cultivadas/efectos de los fármacos , Células Cultivadas/metabolismo , Células Cultivadas/virología , Quimiocinas/biosíntesis , Quimiocinas/genética , Citidina Desaminasa , Citosina Desaminasa/fisiología , Proteína 58 DEAD Box , Proteínas Ligadas a GPI/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Transcriptasa Inversa del VIH/análisis , VIH-1/enzimología , Humanos , Inmunidad Innata , Interferón-alfa/biosíntesis , Interferón-alfa/genética , Interferón beta/biosíntesis , Interferón beta/genética , Ligandos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Monocitos/citología , ARN Bicatenario/inmunología , ARN Viral/inmunología , Receptores CCR5/fisiología , Receptores Inmunológicos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Replicación Viral/efectos de los fármacosRESUMEN
The HIV-1 accessory protein Vif hijacks a cellular Cullin-RING ubiquitin ligase, CRL5, to promote degradation of the APOBEC3 (A3) family of restriction factors. Recently, the cellular transcription cofactor CBFß was shown to form a complex with CRL5-Vif and to be essential for A3 degradation and viral infectivity. We now demonstrate that CBFß is required for assembling a well-ordered CRL5-Vif complex by inhibiting Vif oligomerization and by activating CRL5-Vif via direct interaction. The CRL5-Vif-CBFß holoenzyme forms a well-defined heterohexamer, indicating that Vif simultaneously hijacks CRL5 and CBFß. Heterodimers of CBFß and RUNX transcription factors contribute toward the regulation of genes, including those with immune system functions. We show that binding of Vif to CBFß is mutually exclusive with RUNX heterodimerization and impacts the expression of genes whose regulatory domains are associated with RUNX1. Our results provide a mechanism by which a pathogen with limited coding capacity uses one factor to hijack multiple host pathways.
Asunto(s)
Factor de Unión a CCAAT/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Citosina Desaminasa/metabolismo , Regulación de la Expresión Génica , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/metabolismo , Desaminasas APOBEC , Secuencia de Aminoácidos , Secuencia de Bases , Factor de Unión a CCAAT/química , Factor de Unión a CCAAT/fisiología , Secuencia de Consenso , Subunidad alfa 2 del Factor de Unión al Sitio Principal/química , Subunidad alfa 2 del Factor de Unión al Sitio Principal/fisiología , Citidina Desaminasa , Citosina Desaminasa/química , Citosina Desaminasa/fisiología , Expresión Génica , Genes Reporteros , Células HEK293 , VIH-1/fisiología , Interacciones Huésped-Patógeno , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Datos de Secuencia Molecular , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Multimerización de Proteína , Procesamiento Proteico-Postraduccional , Estabilidad Proteica , Estructura Cuaternaria de Proteína , Linfocitos T/metabolismo , Linfocitos T/virología , Ubiquitinación , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/química , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/fisiologíaRESUMEN
Recent in vivo findings clearly indicate that mammalian cytidine deaminase APOBEC3 can function as a physiological restriction factor to retrotransposons and infectious retroviruses. However, some retroviruses, including primate lentiviruses, have evolved to counter their natural host's APOBEC3. To survive this arms race, primates seem to have acquired multiple copies of APOBEC3 genes. Surprisingly, however, during the process of the diversification of rodent species, as well as the human race, some ancestral individuals acquired genetic variants that reduced the protein levels of APOBEC3 expression, and these variants currently show unexpectedly wide geographic distributions. These data suggest that in the absence of a heavy burden of infectious retroviruses, high-level expression of APOBEC3 cytidine deaminase might be costly to the integrity of the host genome.
Asunto(s)
Citidina Desaminasa/fisiología , Citosina Desaminasa/fisiología , Evolución Molecular , Retroviridae/fisiología , Replicación Viral , Desaminasas APOBEC , Animales , Citidina Desaminasa/genética , Citosina Desaminasa/genética , Duplicación de Gen , Genoma/genética , Interacciones Huésped-Patógeno , Humanos , Ratones , Polimorfismo Genético , Retroviridae/patogenicidadRESUMEN
Retroviruses have long been a fertile model for discovering host-pathogen interactions and their associated biological principles and processes. These advances have not only informed fundamental concepts of viral replication and pathogenesis but have also provided novel insights into host cell biology. This is illustrated by the recent descriptions of host-encoded restriction factors that can serve as effective inhibitors of retroviral replication. Here, we review our understanding of the three restriction factors that have been widely shown to be potent inhibitors of HIV-1: namely, APOBEC3G, TRIM5α, and tetherin. In each case, we discuss how these unrelated proteins were identified, the mechanisms by which they inhibit replication, the means used by HIV-1 to evade their action, and their potential contributions to viral pathogenesis as well as inter- and intraspecies transmission.
Asunto(s)
Antígenos CD/fisiología , Proteínas Portadoras/fisiología , Citosina Desaminasa/fisiología , Infecciones por VIH/virología , VIH-1/fisiología , Desaminasas APOBEC , Factores de Restricción Antivirales , Citidina Desaminasa , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/fisiología , Genes vif/genética , Infecciones por VIH/genética , VIH-1/genética , Interacciones Huésped-Patógeno , Humanos , Mutación/genética , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas , Proteínas Reguladoras y Accesorias Virales/antagonistas & inhibidores , Proteínas Reguladoras y Accesorias Virales/fisiología , Replicación Viral/fisiologíaRESUMEN
Human cells developed the defense systems against retrovirus infections during the evolutions. These systems include retroviral restrictions by DNA cytidine deaminases of APOBEC3 family (A, B, C, DE, F, G, and H), which are potent factors to block the viral replication by blocking reverse transcription and/or integration and by hypermutating viral cDNA. In case of HIV-1, the viral protein, Vif abrogates the APOBEC3F/G function through specific machinery of ubiquitination and proteasomal degradation. Without Vif, APOBEC3F/G are incorporated into virus particles and block reverse transcription and/or integration in a newly infected cell. Recent advances in our understanding about biochemical and structure-biological characteristics of the enzymes provide new insights to reveal more detailed molecular mechanisms for anti-retroviral activity by APOBEC3 family. Here I briefly review how APOBEC3 proteins block retrovirus replications, focusing on APOBEC3G.
Asunto(s)
Antirretrovirales , Citosina Desaminasa/farmacología , Citosina Desaminasa/fisiología , Retroviridae/genética , Retroviridae/fisiología , Replicación Viral/genética , Desaminasas APOBEC , Desaminasa APOBEC-3G , Citidina Desaminasa , Citosina Desaminasa/química , ADN Complementario/genética , ADN Viral/genética , VIH-1 , Humanos , Familia de Multigenes , Mutación , Transcripción Reversa , Ubiquitinación , Integración Viral , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/fisiologíaRESUMEN
Viruses, including retroviruses like human immunodeficiency virus (HIV) and mouse mammary tumor virus (MMTV), are transmitted from mother to infants through milk. Lymphoid cells and antibodies are thought to provide mammary gland and milk-borne immunity. In contrast, little is known about the role of mammary epithelial cells (MECs). The APOBEC3 family of retroviral restriction factors is highly expressed in macrophages and lymphoid and dendritic cells. We now show that APOBEC3 proteins are also expressed in mouse and human MECs. Lymphoid cell-expressed APOBEC3 restricts in vivo spread of MMTV to lymphoid and mammary tissue. In contrast, mammary gland-expressed APOBEC3 is packaged into MMTV virions and decreases the infectivity of milk-borne viruses. Moreover, APOBEC3G and other APOBEC3 genes are expressed in human mammary cells and have the potential to restrict viruses produced in this cell type. These data point to a role for APOBEC3 proteins in limiting infectivity of milk-transmitted viruses.
Asunto(s)
Citidina Desaminasa/fisiología , Células Epiteliales/metabolismo , Glándulas Mamarias Animales/metabolismo , Glándulas Mamarias Humanas/metabolismo , Virus del Tumor Mamario del Ratón/fisiología , Leche/virología , Infecciones por Retroviridae/metabolismo , Desaminasas APOBEC , Animales , Células Cultivadas , Citidina Desaminasa/biosíntesis , Citosina Desaminasa/biosíntesis , Citosina Desaminasa/fisiología , Células Epiteliales/virología , Femenino , VIH-1/patogenicidad , Humanos , Transmisión Vertical de Enfermedad Infecciosa , Linfocitos/metabolismo , Glándulas Mamarias Animales/virología , Glándulas Mamarias Humanas/virología , Virus del Tumor Mamario del Ratón/patogenicidad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/virología , Infecciones por Retroviridae/transmisión , Infecciones por Retroviridae/virología , Infecciones Tumorales por Virus/metabolismo , Infecciones Tumorales por Virus/transmisión , Infecciones Tumorales por Virus/virología , Virión/fisiología , Ensamble de Virus , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/fisiologíaRESUMEN
Tandem stop mutations K26X and H27X in human immunodeficiency virus type 1 (HIV-1) vif compromise virus replication in human T-cell lines that stably express APOBEC3F (A3F) or APOBEC3G (A3G). We previously reported that partial resistance to A3G could develop in these Vif-deficient viruses through a nucleotide A200-to-T/C transversion and a vpr null mutation, but these isolates were still susceptible to restriction by A3F. Here, long-term selection experiments were done to determine how these A3G-selected isolates might evolve to spread in the presence of A3F. We found that A3F, like A3G, is capable of potent, long-term restriction that eventually selects for heritable resistance. In all 7 instances, the selected isolates had restored Vif function to cope with A3F activity. In two isolates, Vif Q26-Q27 and Y26-Q27, the resistance phenotype recapitulated in molecular clones, but when the selected vif alleles were analyzed in the context of an otherwise wild-type viral background, a different outcome emerged. Although HIV-1 clones with Vif Q26-Q27 or Y26-Q27 were fully capable of overcoming A3F, they were now susceptible to restriction by A3G. Concordant with prior studies, a lysine at position 26 proved essential for A3G neutralization. These data combine to indicate that A3F and A3G exert at least partly distinct selective pressures and that Vif function may be essential for the virus to replicate in the presence of A3F.
Asunto(s)
Citosina Desaminasa/fisiología , VIH-1/genética , VIH-1/fisiología , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/fisiología , Desaminasa APOBEC-3G , Alelos , Secuencia de Bases , Línea Celular , Citidina Desaminasa/fisiología , Cartilla de ADN/genética , ADN Viral/genética , Genes vif , VIH-1/patogenicidad , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/fisiología , Humanos , Mutagénesis Sitio-Dirigida , Mutación , Selección Genética , Linfocitos T/fisiología , Linfocitos T/virología , Replicación Viral/genética , Replicación Viral/fisiologíaRESUMEN
We examined a series of site-directed point mutants of human immunodeficiency virus type 1 (HIV-1) Vif for their interaction with cellular anti-viral factors APOBEC3G/APOBEC3F. Mutant viruses that display growth-defect in H9 cells did not counteract effectively APOBEC3G and/or APOBEC3F without exception, as monitored by single-cycle infectivity assays. While growth-defective mutants of Vif C-terminal region were unable to suppress APOBEC3G/APOBEC3F, some N-terminal region mutants did neutralize one of APOBEC3G/APOBEC3F. These data have suggested that members of APOBEC3 family other than APOBEC3G/APOBEC3F are not important for anti-HIV-1 activity. Furthermore, APOPEC3G/APOBEC3F were found to differently associate with Vif in virions as analyzed by equilibrium density centrifugation. Taken together, these results indicated that interaction of HIV-1 Vif and APOBEC3G is distinct from that between Vif and APOBEC3F.
Asunto(s)
Citidina Desaminasa/fisiología , Citosina Desaminasa/fisiología , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/fisiología , Desaminasa APOBEC-3G , Línea Celular , HumanosRESUMEN
To target chemotherapy to tumor vascular endothelial cells (TVECs), we created the AdTie2RprCDFib(knob-RGD+) vector by inserting into an AdEasy adenoviral vector (Ad) backbone: (i) the cytosine deaminase (CD) gene driven by the Tie2 receptor promoter (Tie2Rpr) into the E1 region of Ad; (ii) mutations that reduce binding of the fiber knob to the Coxsackie adenovirus receptor (CAR); and (iii) the RGD peptide into the H1 loop of fiber for binding to the alpha(V)beta(3) integrin receptors on TVECs. To reduce uptake of the AdTie2RprCDFib(knob-RGD+) by reticuloendothelial (RE) and liver cells, we intravenously (i.v.) injected Hetastarch and low-dose Ad (one million vector particles (VPs)) prior to i.v. injection of a therapeutic dose (one billion VPs) of the AdTie2RprCDFib(knob-RGD+) vector. This treatment induced regressions of N202 breast cancer and B16 melanoma without toxicity to normal tissues. We showed that the tumor regression was induced by infection of the TVECs and not by the infection of tumor cells by the AdTie2RprCDFib(knob-RGD+) vector.
Asunto(s)
Neoplasias de la Mama/terapia , Células Endoteliales/metabolismo , Melanoma/terapia , Adenoviridae/genética , Animales , Línea Celular , Línea Celular Tumoral , Citosina Desaminasa/genética , Citosina Desaminasa/fisiología , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Humanos , Melanoma Experimental/terapia , Ratones , Ratones Desnudos , Microscopía Confocal , Regiones Promotoras Genéticas/genética , Receptor TIE-2/genéticaRESUMEN
The interplay between viral and cellular factors determines the outcome of an initial contact between a given virus and its natural host or upon encounter of a novel host. Thus, the potential of inducing disease as well as crossing host species barriers are the consequences of the molecular interactions between the parasite and its susceptible, tolerant or resistant host. Cellular restriction factors, for instance APOBEC3 and TRIM5 proteins, targeting defined pathogens or groups of pathogens as well as viral genes counter-acting these cellular defense systems are of prime importance in this respect and may even represent novel targets for prevention and therapy of virus infections. Due to the importance of host-encoded antiviral restriction and viral counter-defense for pathogenicity and host tropism, the responsible molecular factors and mechanisms are currently under intense investigation. In this review we will introduce host restriction and retroviral counter-defense systems with a special emphasis on the cat and its naturally occurring exogenous retroviruses which is a valid model for human disease, a model that will contribute to increase our basic understanding and potential applications of these important aspects of host-virus interaction.
Asunto(s)
Proteínas Portadoras/fisiología , Enfermedades de los Gatos/virología , Citosina Desaminasa/fisiología , Infecciones por Retroviridae/veterinaria , Retroviridae/fisiología , Animales , Gatos/virología , Interacciones Huésped-Patógeno/fisiología , Virus de la Inmunodeficiencia Felina/fisiología , Lentivirus Felinos/fisiología , Virus de la Leucemia Felina/fisiología , Infecciones por Retroviridae/virología , Integración Viral/fisiología , Replicación Viral/fisiologíaRESUMEN
The ability of human adipose tissue-derived mesenchymal stem cells (AT-MSCs), engineered to express the suicide gene cytosine deaminase::uracil phosphoribosyltransferase (CD::UPRT), to convert the relatively nontoxic 5-fluorocytosine (5-FC) into the highly toxic antitumor 5-fluorouracil (5-FU) together with their ability to track and engraft into tumors and micrometastases makes these cells an attractive tool to activate prodrugs directly within the tumor mass. In this study, we tested the feasibility and efficacy of these therapeutic cells to function as cellular vehicles of prodrug-activating enzymes in prostate cancer (PC) therapy. In in vitro migration experiments we have shown that therapeutic AT-MSCs migrated to all the prostate cell lines tested. In a pilot preclinical study, we observed that coinjections of human bone metastatic PC cells along with the transduced AT-MSCs into nude mice treated with 5-FC induced a complete tumor regression in a dose dependent manner or did not even allow the establishment of the tumor. More importantly, we also demonstrated that the therapeutic cells were effective in significantly inhibiting PC tumor growth after intravenous administration that is a key requisite for any clinical application of gene-directed enzyme prodrug therapies.
Asunto(s)
Citosina Desaminasa/fisiología , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/fisiología , Pentosiltransferasa/fisiología , Neoplasias de la Próstata/terapia , Animales , Línea Celular Tumoral , Citosina Desaminasa/genética , Flucitosina/farmacología , Fluorouracilo/farmacología , Humanos , Masculino , Células Madre Mesenquimatosas/citología , Ratones , Ratones Desnudos , Pentosiltransferasa/genética , Neoplasias de la Próstata/inducido químicamenteRESUMEN
Previously, we have shown that the genetically modified human neural stem cells (NSCs) show remarkable migratory and tumor-tropic capability to track down brain tumor cells and deliver therapeutic agents with significant therapeutic benefit. Human NSCs that were retrovirally transduced with cytosine deaminase (CD) gene showed remarkable 'bystander killer effect' on the glioma cells after application of the prodrug, 5-fluorocytosine (5-FC). Interferon-beta (IFN-beta) is known for its antiproliferative effects in a variety of cancers. In our pilot clinical trial in glioma, the IFN-beta gene has shown potent antitumor activity in patients with malignant glioma. In the present study, we sought to examine whether human NSCs genetically modified to express both CD and IFN-beta genes intensified antitumor effect on experimental glioma. In vitro studies showed that CD/IFN-beta-expressing NSCs exerted a remarkable bystander effect on human glioma cells after the application of 5-FC, as compared with parental NSCs and CD-expressing NSCs. In animal models with human glioma orthotopic xenograft, intravenously infused CD/IFN-beta-expressing NSCs produced striking antitumor effect after administration of the prodrug 5-FC. Furthermore, the same gene therapy regimen prolonged survival periods significantly in the experimental animals. The results of the present study indicate that the multimodal NSC-based treatment strategy might have therapeutic potential against gliomas.
Asunto(s)
Citosina Desaminasa/fisiología , Terapia Genética/métodos , Glioma/tratamiento farmacológico , Glioma/terapia , Interferón beta/fisiología , Animales , Efecto Espectador , Línea Celular Tumoral , Citosina Desaminasa/genética , Modelos Animales de Enfermedad , Femenino , Flucitosina/uso terapéutico , Humanos , Interferón beta/genética , Ratones , Ratones DesnudosRESUMEN
Several variants of APOBEC3H (A3H) have been identified in different human populations. Certain variants of this protein are particularly potent inhibitors of retrotransposons and retroviruses, including HIV-1. However, it is not clear whether HIV-1 Vif can recognize and suppress the antiviral activity of A3H variants, as it does with other APOBEC3 proteins. We now report that A3H_Haplotype II (HapII), a potent inhibitor of HIV-1 in the absence of Vif, can indeed be degraded by HIV-1 Vif. Vif-induced degradation of A3H_HapII was blocked by the proteasome inhibitor MG132 and a Cullin5 (Cul5) dominant negative mutant. In addition, Vif mutants that were incapable of assembly with the host E3 ligase complex factors Cul5, ElonginB, and ElonginC were also defective for A3H_HapII suppression. Although we found that Vif hijacks the same E3 ligase to degrade A3H_HapII as it does to inactivate APOBEC3G (A3G) and APOBEC3F (A3F), more Vif motifs were involved in A3H_HapII inactivation than in either A3G or A3F suppression. In contrast to A3H_HapII, A3H_Haplotype I (HapI), which differs in only three amino acids from A3H_HapII, was resistant to HIV-1 Vif-mediated degradation. We also found that residue 121 was critical for determining A3H sensitivity and binding to HIV-1 Vif.
Asunto(s)
Citosina Desaminasa/genética , Citosina Desaminasa/fisiología , Variación Genética , VIH-1/fisiología , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/fisiología , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Aminohidrolasas , Secuencia de Bases , Línea Celular , Citosina Desaminasa/antagonistas & inhibidores , Citosina Desaminasa/química , Genes vif , VIH-1/genética , VIH-1/patogenicidad , Haplotipos , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/fisiología , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Plásmidos/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Estructura Terciaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homología de Secuencia de Aminoácido , Transfección , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/química , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
The arms race between virus and host is a constant battle. APOBEC3 proteins are known to be potent innate cellular defenses against both endogenous retroelements and diverse retroviruses. However, retroviruses have developed their own methods to launch counter-strikes. Most primate lentiviruses encode a protein called the viral infectivity factor (Vif). Vif induces targeted destruction of APOBEC3 proteins by hijacking the cellular ubiquitin-proteasome pathway. Here we review the research that led up to the identification of A3G, the mechanisms by which APOBEC3 proteins can inhibit retroelements, and the counter-mechanisms that HIV-1 Vif has developed to evade its antiviral activities.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/prevención & control , Citosina Desaminasa/fisiología , VIH-1 , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/fisiología , Desaminasas APOBEC , Ciclo Celular , Citidina Desaminasa , Humanos , Evasión Inmune , Complejo de la Endopetidasa Proteasomal/fisiologíaRESUMEN
Gene directed enzyme prodrug therapy (GDEPT) of cancer aims to improve the selectivity of chemotherapy by gene transfer, thus enabling target cells to convert nontoxic prodrugs to cytotoxic drugs. A zone of cell kill around gene-modified cells due to transfer of toxic metabolites, known as the bystander effect, leads to tumour regression. Here we discuss the implications of either striving for a strong bystander effect to overcome poor gene transfer, or avoiding the bystander effect to reduce potential systemic effects, with the aid of three successful GDEPT systems. This review concentrates on bystander effects and drug development with regard to these enzyme prodrug combinations, namely herpes simplex virus thymidine kinase (HSV-TK) with ganciclovir (GCV), cytosine deaminase (CD) from bacteria or yeast with 5-fluorocytodine (5-FC), and bacterial nitroreductase (NfsB) with 5-(azaridin-1-yl)-2,4-dinitrobenzamide (CB1954), and their respective derivatives.
Asunto(s)
Terapia Genética/métodos , Profármacos/uso terapéutico , Animales , Aziridinas/uso terapéutico , Citosina Desaminasa/genética , Citosina Desaminasa/fisiología , Flucitosina/uso terapéutico , Ganciclovir/uso terapéutico , Humanos , Nitrorreductasas/genética , Nitrorreductasas/fisiología , Timidina Quinasa/genéticaRESUMEN
HIV-1 infections and the resulting AIDS pandemic remain a global challenge in the absence of a protective vaccine and because of rapid selection of drug-resistant viral variants in response to all currently available antiviral therapies. The development of new and highly active antiviral agents would greatly facilitate effective clinical management of HIV-1 infections and delay the onset of AIDS. Recent advances in our understanding of intracellular immunity conferred by host cytidine deaminases APOBEC3G (A3G) and APOBEC3F (A3F) and the mechanism by which the virally encoded virion infectivity factor (Vif) protein induces their proteasomal degradation provide fresh opportunities for the development of novel antiviral treatments. Interestingly, the Vif-A3G and Vif-A3F interactions that overcome this host defense mechanism are structurally distinct and provide two potential targets for antiviral drug development. This review provides an overview of current knowledge of APOBEC3-Vif interactions and recent efforts to target these interactions for antiviral drug development.
Asunto(s)
Fármacos Anti-VIH/farmacología , Citosina Desaminasa/fisiología , Infecciones por VIH/metabolismo , VIH-1/fisiología , Virión/metabolismo , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/metabolismo , Desaminasas APOBEC , Fármacos Anti-VIH/uso terapéutico , Citidina Desaminasa , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Virión/genética , Replicación Viral , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen vpr del Virus de la Inmunodeficiencia HumanaRESUMEN
Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like (APOBEC) proteins are members of a protein family sharing the common characteristic of cytidine deaminase activity. The antiviral activity of APOBEC3G and APOBEC3F has been studied more extensively than that of the other members of this family. The antiviral activity of APOBEC3B and APOBEC3DE has also been described. Studies of other APOBEC proteins have not revealed any antiviral activities against HIV-1; however, further investigation is required. In the absence of human immunodeficiency virus type 1 (HIV-1) virion infectivity factor (Vif), APOBEC3G and APOBEC3F are incorporated into HIV-1 virions and hypermutate the viral genomic DNA by their cytidine deaminase activity. HIV-1 Vif protein suppresses the antiviral role of APOBEC proteins by several mechanisms that lead to inhibition of incorporation of APOBEC3G/3F into HIV-1 virions. The detailed mechanisms involved in the suppression of APOBEC proteins by Vif are still being elucidated. Novel studies in which as yet undefined aspects of the suppression of APOBEC proteins are investigated could reveal important and potentially exploitable information for addressing HIV-1 infection in humans.