RESUMEN
How SIV progenitors evolved into deadly HIV-1 and HIV-2 following initial cross-species transmission still remains a mystery. Here, we used humanized mice as a human surrogate system to evaluate SIVsm evolution into HIV-2. Increased viral virulence to human CD4+ T cells and adaptive genetic changes were observed during serial passages.
Asunto(s)
Cercocebus atys/virología , Modelos Animales de Enfermedad , VIH-2/crecimiento & desarrollo , VIH-2/genética , Animales , Humanos , Ratones , Pase Seriado , Virus de la Inmunodeficiencia de los Simios , Carga ViralRESUMEN
In contrast to infections with human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques, SIV infection of a natural host, sooty mangabeys (Cercocebus atys), is non-pathogenic despite high viraemia. Here we sequenced and assembled the genome of a captive sooty mangabey. We conducted genome-wide comparative analyses of transcript assemblies from C. atys and AIDS-susceptible species, such as humans and macaques, to identify candidates for host genetic factors that influence susceptibility. We identified several immune-related genes in the genome of C. atys that show substantial sequence divergence from macaques or humans. One of these sequence divergences, a C-terminal frameshift in the toll-like receptor-4 (TLR4) gene of C. atys, is associated with a blunted in vitro response to TLR-4 ligands. In addition, we found a major structural change in exons 3-4 of the immune-regulatory protein intercellular adhesion molecule 2 (ICAM-2); expression of this variant leads to reduced cell surface expression of ICAM-2. These data provide a resource for comparative genomic studies of HIV and/or SIV pathogenesis and may help to elucidate the mechanisms by which SIV-infected sooty mangabeys avoid AIDS.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/genética , Cercocebus atys/genética , Cercocebus atys/virología , Predisposición Genética a la Enfermedad , Genoma/genética , Especificidad del Huésped/genética , Virus de la Inmunodeficiencia de los Simios , Síndrome de Inmunodeficiencia Adquirida/virología , Secuencia de Aminoácidos , Animales , Moléculas de Adhesión Celular/química , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Cercocebus atys/inmunología , Exones/genética , Femenino , Mutación del Sistema de Lectura/genética , Variación Genética , Genómica , VIH/patogenicidad , Humanos , Macaca/virología , Eliminación de Secuencia , Síndrome de Inmunodeficiencia Adquirida del Simio/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Especificidad de la Especie , Receptor Toll-Like 4/química , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Transcriptoma/genética , Secuenciación Completa del GenomaRESUMEN
HIV-2 is thought to have originated from an SIV progenitor native to sooty mangabeys. To model the initial human transmission and understand the sequential viral evolution, humanized mice were infected with SIVsm and serially passaged for five generations. Productive infection was seen by week 3 during the initial challenge followed by chronic viremia and gradual CD4+ T cell decline. Viral loads increased by the 5th generation resulting in more rapid CD4+ T cell decline. Genetic analysis revealed several amino acid substitutions that were nonsynonymous and fixed in multiple hu-mice across each of the 5 generations in the nef, env and rev regions. The highest rate of substitution occurred in the nef and env regions and most were observed within the first two generations. These data demonstrated the utility of hu-mice in modeling the SIVsm transmission to the human and to evaluate its potential sequential evolution into a human pathogen of HIV-2 lineage.
Asunto(s)
Cercocebus atys/virología , Evolución Molecular , VIH-2/crecimiento & desarrollo , VIH-2/genética , Virus de la Inmunodeficiencia de los Simios/crecimiento & desarrollo , Virus de la Inmunodeficiencia de los Simios/genética , Sustitución de Aminoácidos , Animales , Recuento de Linfocito CD4 , Humanos , Ratones , Ratones SCID , Modelos Biológicos , Pase Seriado , Carga Viral , Proteínas Virales/genéticaRESUMEN
BACKGROUND: Epidemic HIV-2 (groups A and B) emerged in humans circa 1930-40. Its closest ancestors are SIVsmm infecting sooty mangabeys from southwestern Côte d'Ivoire. The earliest large-scale serological surveys of HIV-2 in West Africa (1985-91) show a patchy spread. Côte d'Ivoire and Guinea-Bissau had the highest prevalence rates by then, and phylogeographical analysis suggests they were the earliest epicenters. Wars and parenteral transmission have been hypothesized to have promoted HIV-2 spread. Male circumcision (MC) is known to correlate negatively with HIV-1 prevalence in Africa, but studies examining this issue for HIV-2 are lacking. METHODS: We reviewed published HIV-2 serosurveys for 30 cities of all West African countries and obtained credible estimates of real prevalence through Bayesian estimation. We estimated past MC rates of 218 West African ethnic groups, based on ethnographic literature and fieldwork. We collected demographic tables specifying the ethnic partition in cities. Uncertainty was incorporated by defining plausible ranges of parameters (e.g. timing of introduction, proportion circumcised). We generated 1,000 sets of past MC rates per city using Latin Hypercube Sampling with different parameter combinations, and explored the correlation between HIV-2 prevalence and estimated MC rate (both logit-transformed) in the 1,000 replicates. RESULTS AND CONCLUSIONS: Our survey reveals that, in the early 20th century, MC was far less common and geographically more variable than nowadays. HIV-2 prevalence in 1985-91 and MC rates in 1950 were negatively correlated (Spearman rho = -0.546, IQR: -0.553--0.546, p≤0.0021). Guinea-Bissau and Côte d'Ivoire cities had markedly lower MC rates. In addition, MC was uncommon in rural southwestern Côte d'Ivoire in 1930.The differential HIV-2 spread in West Africa correlates with different historical MC rates. We suggest HIV-2 only formed early substantial foci in cities with substantial uncircumcised populations. Lack of MC in rural areas exposed to bushmeat may have had a role in successful HIV-2 emergence.
Asunto(s)
Infecciones por VIH/epidemiología , VIH-2/patogenicidad , Síndrome de Inmunodeficiencia Adquirida/epidemiología , Síndrome de Inmunodeficiencia Adquirida/virología , Animales , Cercocebus atys/virología , Circuncisión Masculina/métodos , Côte d'Ivoire/epidemiología , Países en Desarrollo , Epidemias , Guinea Bissau/epidemiología , Infecciones por VIH/virología , VIH-1/patogenicidad , Humanos , Masculino , Filogeografía/métodos , PrevalenciaRESUMEN
In the 20th century, thirteen distinct human immunodeficiency viruses emerged following independent cross-species transmission events involving simian immunodeficiency viruses (SIV) from African primates. In the late 1900s, pathogenic SIV strains also emerged in the United Sates among captive Asian macaque species following their unintentional infection with SIV from African sooty mangabeys (SIVsmm). Since their discovery in the 1980s, SIVs from rhesus macaques (SIVmac) and pig-tailed macaques (SIVmne) have become invaluable models for studying HIV pathogenesis, vaccine design and the emergence of viruses. SIV isolates from captive crab-eating macaques (SIVmfa) were initially described but lost prior to any detailed molecular and genetic characterization. In order to infer the origins of the lost SIVmfa lineage, we located archived material and colony records, recovered its genomic sequence by PCR, and assessed its phylogenetic relationship to other SIV strains. We conclude that SIVmfa is the product of two cross-species transmission events. The first was the established transmission of SIVsmm to rhesus macaques, which occurred at the California National Primate Research Center in the late 1960s and the virus later emerged as SIVmac. In a second event, SIVmac was transmitted to crab-eating macaques, likely at the Laboratory for Experimental Medicine and Surgery in Primates in the early 1970s, and it was later spread to the New England Primate Research Center colony in 1973 and eventually isolated in 1986. Our analysis suggests that SIVmac had already emerged by the early 1970s and had begun to diverge into distinct lineages. Furthermore, our findings suggest that pathogenic SIV strains may have been more widely distributed than previously appreciated, raising the possibility that additional isolates may await discovery.
Asunto(s)
Macaca fascicularis/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Animales , Cercocebus atys/virología , Modelos Animales de Enfermedad , Genoma Viral/genética , Macaca nemestrina/virología , FilogeniaRESUMEN
To explore the differences between the extreme SIV infection phenotypes, nonprogression (BEN: benign) to AIDS in sooty mangabeys (SMs) and progression to AIDS (MAL: malignant) in rhesus macaques (RMs), we performed an integrated dual positive-negative connectivity (DPNC) analysis of gene coexpression networks (GCN) based on publicly available big data sets in the GEO database of NCBI. The microarray-based gene expression data sets were generated, respectively, from the peripheral blood of SMs and RMs at several time points of SIV infection. Significant differences of GCN changes in DPNC values were observed in SIV-infected SMs and RMs. There are three groups of enriched genes or pathways (EGPs) that are associated with three SIV infection phenotypes (BEN+, MAL+ and mixed BEN+/MAL+). The MAL+ phenotype in SIV-infected RMs is specifically associated with eight EGPs, including the protein ubiquitin proteasome system, p53, granzyme A, gramzyme B, polo-like kinase, Glucocorticoid receptor, oxidative phosyphorylation and mitochondrial signaling. Mitochondrial (endosymbiotic) dysfunction is solely present in RMs. Specific BEN+ pattern changes in four EGPs are identified in SIV-infected SMs, including the pathways contributing to interferon signaling, BRCA1/DNA damage response, PKR/INF induction and LGALS8. There are three enriched pathways (PRR-activated IRF signaling, RIG1-like receptor and PRR pathway) contributing to the mixed (BEN+/MAL+) phenotypes of SIV infections in RMs and SMs, suggesting that these pathways play a dual role in the host defense against viral infections. Further analysis of Hub genes in these GCNs revealed that the genes LGALS8 and IL-17RA, which positively regulate the barrier function of the gut mucosa and the immune homeostasis with the gut microbiota (exosymbiosis), were significantly differentially expressed in RMs and SMs. Our data suggest that there exists an exo- (dysbiosis of the gut microbiota) and endo- (mitochondrial dysfunction) symbiotic imbalance (EESI) in HIV/SIV infections. Dissecting the mechanisms of the exo-endo symbiotic balance (EESB) that maintains immune homeostasis and the EESI problems in HIV/SIV infections may lead to a better understanding of the pathogenesis of AIDS and the development of novel interventions for the rational control of this disease.
Asunto(s)
Cercocebus atys/genética , Redes Reguladoras de Genes , Macaca mulatta/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/genética , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Cercocebus atys/inmunología , Cercocebus atys/virología , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Macaca mulatta/inmunología , Macaca mulatta/virología , Análisis de Secuencia por Matrices de Oligonucleótidos , Transducción de Señal , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Especificidad de la EspecieRESUMEN
UNLABELLED: Macrophages are target cells of HIV/SIV infection that may play a role in AIDS pathogenesis and contribute to the long-lived reservoir of latently infected cells during antiretroviral therapy (ART). In previous work, we and others have shown that during pathogenic SIV infection of rhesus macaques (RMs), rapid disease progression is associated with high levels of in vivo macrophage infection. In contrast, during nonpathogenic SIV infection of sooty mangabeys (SMs), neither spontaneous nor experimental CD4(+) T cell depletion results in substantial levels of in vivo macrophage infection. To test the hypothesis that SM macrophages are intrinsically more resistant to SIV infection than RM macrophages, we undertook an in vitro comparative assessment of monocyte-derived macrophages (MDMs) from both nonhuman primate species. Using the primary isolate SIVM949, which replicates well in lymphocytes from both RMs and SMs, we found that infection of RM macrophages resulted in persistent SIV-RNA production while SIV-RNA levels in SM macrophage cultures decreased 10- to 100-fold over a similar temporal course of in vitro infection. To explore potential mechanisms responsible for the lower levels of SIV replication and/or production in macrophages from SMs we comparatively assessed, in the two studied species, the expression of the SIV coreceptor as well as the expression of a number of host restriction factors. While previous studies showed that SM monocytes express lower levels of CCR5 (but not CD4) than RM monocytes, the level of CCR5 expression in MDMs was similar in the two species. Interestingly, we found that SM macrophages exhibited a significantly greater increase in the expression of tetherin (P = 0.003) and TRIM22 (P = 0.0006) in response to alpha interferon stimulation and increased expression of multiple host restriction factors in response to lipopolysaccharide stimulation and exposure to SIV. Overall, these findings confirm, in an in vitro infection system, that SM macrophages are relatively more resistant to SIV infection compared to RM macrophages, and suggest that a combination of entry and postentry restriction mechanisms may protect these cells from productive SIV infection. IMPORTANCE: This manuscript represents the first in vivo comparative analysis of monocyte-derived macrophages (MDMs) between rhesus macaques, i.e., experimental SIV hosts in which the infection is pathogenic and macrophages can be infected, and sooty mangabeys, i.e., natural SIV hosts in which the infection is nonpathogenic and macrophages are virtually never infected in vivo. This study demonstrates that mangabey-derived MDMs are more resistant to SIV infection in vitro compared to macaque-derived MDMs, and provides a potential explanation for this observation by showing increased expression of specific retrovirus restriction factors in mangabey-derived macrophages. Overall, this study is important as it contributes to our understanding of why SIV infection is nonpathogenic in sooty mangabeys while it is pathogenic in macaques, and is consistent with a pathogenic role for in vivo macrophage infection during pathogenic lentiviral infection.
Asunto(s)
Cercocebus atys/virología , Macaca mulatta/virología , Macrófagos/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Replicación Viral/genética , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/virología , Cercocebus atys/inmunología , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/inmunología , Regulación de la Expresión Génica , Especificidad del Huésped , Interacciones Huésped-Patógeno , Interferón-alfa/farmacología , Lipopolisacáridos/farmacología , Activación de Linfocitos , Macaca mulatta/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/patología , Macrófagos/virología , Cultivo Primario de Células , Receptores CCR5/genética , Receptores CCR5/inmunología , Transducción de Señal , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Virus de la Inmunodeficiencia de los Simios/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Carga ViralRESUMEN
We isolated a monkeypox virus from a wild-living monkey, a sooty mangabey, found dead in Taï National Park, Côte d'Ivoire, in March 2012. The whole-genome sequence obtained from this isolate and directly from clinical specimens showed its close relationship to monkeypox viruses from Western Africa.
Asunto(s)
Cercocebus atys/virología , Genoma Viral , Monkeypox virus/genética , Mpox/virología , Filogenia , Animales , Animales Recién Nacidos , Côte d'Ivoire , Resultado Fatal , Secuenciación de Nucleótidos de Alto Rendimiento , Monkeypox virus/clasificación , Monkeypox virus/aislamiento & purificación , FilogeografíaRESUMEN
Mother-to-infant transmission (MTIT) of HIV is a serious global health concern, with over 300,000 children newly infected in 2011. SIV infection of rhesus macaques (RMs) results in similar rates of MTIT to that of HIV in humans. In contrast, SIV infection of sooty mangabeys (SMs) rarely results in MTIT. The mechanisms underlying protection from MTIT in SMs are unknown. In this study we tested the hypotheses that breast milk factors and/or target cell availability dictate the rate of MTIT in RMs (transmitters) and SMs (non-transmitters). We measured viral loads (cell-free and cell-associated), levels of immune mediators, and the ability to inhibit SIV infection in vitro in milk obtained from lactating RMs and SMs. In addition, we assessed the levels of target cells (CD4+CCR5+ T cells) in gastrointestinal and lymphoid tissues, including those relevant to breastfeeding transmission, as well as peripheral blood from uninfected RM and SM infants. We found that frequently-transmitting RMs did not have higher levels of cell-free or cell-associated viral loads in milk compared to rarely-transmitting SMs. Milk from both RMs and SMs moderately inhibited in vitro SIV infection, and presence of the examined immune mediators in these two species did not readily explain the differential rates of transmission. Importantly, we found that the percentage of CD4+CCR5+ T cells was significantly lower in all tissues in infant SMs as compared to infant RMs despite robust levels of CD4+ T cell proliferation in both species. The difference between the frequently-transmitting RMs and rarely-transmitting SMs was most pronounced in CD4+ memory T cells in the spleen, jejunum, and colon as well as in central and effector memory CD4+ T cells in the peripheral blood. We propose that limited availability of SIV target cells in infant SMs represents a key evolutionary adaptation to reduce the risk of MTIT in SIV-infected SMs.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Cercocebus atys/inmunología , Macaca mulatta/inmunología , Leche/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/transmisión , Animales , Cercocebus atys/virología , Femenino , Lactancia , Macaca mulatta/virología , Embarazo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunologíaRESUMEN
Lentiviruses contain accessory genes that have evolved to counteract the effects of host cellular defence proteins that inhibit productive infection. One such restriction factor, SAMHD1, inhibits human immunodeficiency virus (HIV)-1 infection of myeloid-lineage cells as well as resting CD4(+) T cells by reducing the cellular deoxynucleoside 5'-triphosphate (dNTP) concentration to a level at which the viral reverse transcriptase cannot function. In other lentiviruses, including HIV-2 and related simian immunodeficiency viruses (SIVs), SAMHD1 restriction is overcome by the action of viral accessory protein x (Vpx) or the related viral protein r (Vpr) that target and recruit SAMHD1 for proteasomal degradation. The molecular mechanism by which these viral proteins are able to usurp the host cell's ubiquitination machinery to destroy the cell's protection against these viruses has not been defined. Here we present the crystal structure of a ternary complex of Vpx with the human E3 ligase substrate adaptor DCAF1 and the carboxy-terminal region of human SAMHD1. Vpx is made up of a three-helical bundle stabilized by a zinc finger motif, and wraps tightly around the disc-shaped DCAF1 molecule to present a new molecular surface. This adapted surface is then able to recruit SAMHD1 via its C terminus, making it a competent substrate for the E3 ligase to mark for proteasomal degradation. The structure reported here provides a molecular description of how a lentiviral accessory protein is able to subvert the cell's normal protein degradation pathway to inactivate the cellular viral defence system.
Asunto(s)
Proteínas Portadoras/metabolismo , VIH/química , VIH/fisiología , Proteínas de Unión al GTP Monoméricas/metabolismo , Proteolisis , Proteínas Reguladoras y Accesorias Virales/química , Proteínas Reguladoras y Accesorias Virales/metabolismo , Secuencia de Aminoácidos , Animales , Proteínas Portadoras/química , Cercocebus atys/virología , Cristalografía por Rayos X , Interacciones Huésped-Patógeno , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Proteínas de Unión al GTP Monoméricas/química , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Serina-Treonina Quinasas , Proteína 1 que Contiene Dominios SAM y HD , Virus de la Inmunodeficiencia de los Simios/química , Virus de la Inmunodeficiencia de los Simios/fisiología , Ubiquitina-Proteína Ligasas , Ubiquitinación , Productos del Gen vpr del Virus de la Inmunodeficiencia Humana/química , Productos del Gen vpr del Virus de la Inmunodeficiencia Humana/metabolismoRESUMEN
HIV-1 in humans resulted from at least four cross-species transmissions of simian immunodeficiency viruses (SIVs) from chimpanzees and gorillas in West Central Africa, while HIV-2 viruses resulted from at least eight independent transmissions of SIVs infecting sooty mangabeys in West Africa only, where one of these transmissions (HIV-1 group M) is responsible for the global epidemic. HIV-1 M is subdivided into nine subtypes and a wide diversity of circulating recombinant forms (CRFs) and unique recombinant forms. The heterogenic HIV-1 M subtype/CRF distribution is the result of founder effects. The genetic diversity of HIV-1 continues to increase overtime due to demographic factors such as travel and migration and frequent co/superinfections. In addition, the expanded access to antiretrovirals leads to an increasing number of drug-resistant strains, especially in resource limited countries.
Asunto(s)
Infecciones por VIH/epidemiología , VIH-1/clasificación , VIH-2/clasificación , Epidemiología Molecular , Virus Reordenados/clasificación , Virus de la Inmunodeficiencia de los Simios/clasificación , África/epidemiología , Animales , Cercocebus atys/virología , Farmacorresistencia Viral , Variación Genética , Gorilla gorilla/virología , Infecciones por VIH/transmisión , Infecciones por VIH/virología , VIH-1/genética , VIH-2/genética , Humanos , Pan troglodytes/virología , Filogenia , Virus Reordenados/genética , Virus de la Inmunodeficiencia de los Simios/genéticaRESUMEN
Lymphoid tissue immunopathology is a characteristic feature of chronic HIV/SIV infection in AIDS-susceptible species, but is absent in SIV-infected natural hosts. To investigate factors contributing to this difference, we compared germinal center development and SIV RNA distribution in peripheral lymph nodes during primary SIV infection of the natural host sooty mangabey and the non-natural host pig-tailed macaque. Although SIV-infected cells were detected in the lymph node of both species at two weeks post infection, they were confined to the lymph node paracortex in immune-competent mangabeys but were seen in both the paracortex and the germinal center of SIV-infected macaques. By six weeks post infection, SIV-infected cells were no longer detected in the lymph node of sooty mangabeys. The difference in localization and rate of disappearance of SIV-infected cells between the two species was associated with trapping of cell-free virus on follicular dendritic cells and higher numbers of germinal center CD4(+) T lymphocytes in macaques post SIV infection. Our data suggests that fundamental differences in the germinal center microenvironment prevent productive SIV infection within the lymph node germinal centers of natural hosts contributing to sustained immune competency.
Asunto(s)
Cercocebus atys/inmunología , Centro Germinal/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/metabolismo , Enfermedad Aguda , Animales , Linfocitos T CD4-Positivos/citología , Cercocebus atys/virología , Centro Germinal/virología , Inmunofenotipificación , Ganglios Linfáticos/patología , Macaca , ARN Viral/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Carga ViralRESUMEN
Human immunodeficiency virus type 1 (HIV-1) infection is characterized by persistent viral replication in the context of CD4(+) T cell depletion and elevated immune activation associated with disease progression. In contrast, simian immunodeficiency virus (SIV) infection of African-origin sooty mangabeys (SM) generally does not result in simian AIDS despite high viral loads and therefore affords a unique model in which to study the immunologic contributions to a nonpathogenic lentiviral disease outcome. A key feature of these natural SIV infections is the maintenance of low levels of immune activation during chronic infection. Our goal was to delineate the contribution of monocytes to maintaining low levels of immune activation in SIV-infected SM. Utilizing an ex vivo whole-blood assay, proinflammatory cytokine production was quantified in monocytes in response to multiple Toll-like receptor (TLR) ligands and a specific, significant reduction in the tumor necrosis factor alpha (TNF-α) response to lipopolysaccharide (LPS) was observed in SIV-infected SM. In contrast, monocytes from hosts of pathogenic infections (HIV-infected humans and SIV-infected Asian macaques) maintained a robust TNF-α response. In SIV-infected SM, monocyte TNF-α responses to low levels of LPS could be augmented by the presence of plasma from uninfected control animals. The impact of LPS-induced TNF-α production on immune activation was demonstrated in vitro, as TNF-α blocking antibodies inhibited downstream CD8(+) T cell activation in a dose-dependent manner. These data demonstrate an association between nonpathogenic SIV infection of SM and a reduced monocyte TNF-α response to LPS, and they identify a role for monocytes in contributing to the suppressed chronic immune activation observed in these natural hosts.
Asunto(s)
Cercocebus atys/inmunología , Activación de Linfocitos , Monocitos/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Linfocitos T CD8-positivos/inmunología , Cercocebus atys/virología , VIH-1/inmunología , Humanos , Interleucina-10/genética , Lipopolisacáridos/inmunología , Monocitos/metabolismo , Fagocitosis , Fitohemaglutininas/inmunología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Virus de la Inmunodeficiencia de los Simios/metabolismo , Ácidos Teicoicos/inmunología , Receptor Toll-Like 4/genética , Factor de Necrosis Tumoral alfa/genética , Carga ViralRESUMEN
A key feature differentiating nonpathogenic SIV infection of sooty mangabeys (SMs) from pathogenic HIV/SIV infections is the rapid resolution of type I IFN (IFN-I) responses and IFN-stimulated gene expression during the acute-to-chronic phase transition and the establishment of an immune quiescent state that persists throughout the chronic infection. We hypothesized that low levels of IFN-I signaling may help to prevent chronic immune activation and disease progression in SIV-infected SMs. To assess the effects of IFN-I signaling in this setting, in the present study, we administered recombinant rhesus macaque IFNα2-IgFc (rmIFNα2) to 8 naturally SIV-infected SMs weekly for 16 weeks. Gene-expression profiling revealed a strong up-regulation of IFN-stimulated genes in the blood of treated animals, confirming the reagent's bioactivity. Interestingly, we observed an approximately 1-log decrease in viral load that persisted through day 35 of treatment. Flow cytometric analysis of lymphocytes in the blood, lymph nodes, and rectal biopsies did not reveal a significant decline of CD4(+) T cells, a robust increase in lymphocyte activation, or change in the level of SIV-specific CD8(+) T cells. The results of the present study indicate that administration of type I IFNs in SIV-infected SMs induces a significant anti-viral effect that is not associated with a detectable increase in chronic immune activation.
Asunto(s)
Cercocebus atys/virología , Interferón Tipo I/agonistas , Activación de Linfocitos/efectos de los fármacos , Proteínas Recombinantes/farmacología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/fisiología , Replicación Viral/efectos de los fármacos , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Proliferación Celular/efectos de los fármacos , Cercocebus atys/sangre , Cercocebus atys/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interferón Tipo I/administración & dosificación , Interferón Tipo I/farmacología , Depleción Linfocítica , Macaca mulatta/inmunología , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida del Simio/sangre , 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 , Especificidad de la Especie , Carga Viral/efectos de los fármacos , Viremia/sangre , Viremia/inmunología , Viremia/virologíaRESUMEN
PURPOSE OF REVIEW: This review summarizes the role of CD3+CD4-CD8- double-negative T cells, which have both regulatory and helper T-cell functions and may have the potential to compensate for the reduced levels of CD4 T cells during SIV/HIV infection. RECENT FINDINGS: Double-negative T cells have been characterized in several human diseases and in murine models of autoimmunity and transplantation, where they exhibit both immunoregulatory and helper T-cell-like function. During the natural nonpathogenic SIV infection of African nonhuman primates, the lack of clinical disease progression is associated with the presence of double-negative T cells that maintain helper T-cell functions while remaining refractory to viral infection. Moreover, DN T cells may compensate for very low levels of CD4+ T cells observed in a cohort of SIV-infected sooty mangabeys that have remained free of clinical AIDS for over 10 years. These studies identify a potential for double-negative T cells to provide critical helper function during HIV infection. SUMMARY: Double-negative T cells with some CD4+ T-cell functions are associated with a nonpathogenic outcome during SIV infection and represent a potential immune therapeutic target in HIV-infected patients.
Asunto(s)
Complejo CD3/metabolismo , Infecciones por VIH/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Animales , Cercocebus atys/virología , Estudios de Cohortes , Progresión de la Enfermedad , Infecciones por VIH/fisiopatología , Infecciones por VIH/virología , VIH-1/inmunología , Humanos , Macaca mulatta , Enfermedades de los Monos/inmunología , Enfermedades de los Monos/fisiopatología , Enfermedades de los Monos/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/fisiopatología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/inmunología , Linfocitos T/inmunologíaRESUMEN
Natural host sooty mangabeys (SM) infected with simian immunodeficiency virus SIVsmm do not develop AIDS despite high viremia. SM and other natural hosts express very low levels of CCR5 on CD4(+) T cells, and we recently showed that SIVsmm infection and robust replication occur in vivo in SM genetically lacking CCR5, indicating the use of additional entry pathways. SIVsmm uses several alternative coreceptors of human origin in vitro, but which molecules of SM origin support entry is unknown. We cloned a panel of putative coreceptors from SM and tested their ability to mediate infection, in conjunction with smCD4, by pseudotypes carrying Envs from multiple SIVsmm subtypes. smCXCR6 supported efficient infection by all SIVsmm isolates with entry levels comparable to those for smCCR5, and smGPR15 enabled entry by all isolates at modest levels. smGPR1 and smAPJ supported low and variable entry, whereas smCCR2b, smCCR3, smCCR4, smCCR8, and smCXCR4 were not used by most isolates. In contrast, SIVsmm from rare infected SM with profound CD4(+) T cell loss, previously reported to have expanded use of human coreceptors, including CXCR4, used smCXCR4, smCXCR6, and smCCR5 efficiently and also exhibited robust entry through smCCR3, smCCR8, smGPR1, smGPR15, and smAPJ. Entry was similar with both known alleles of smCD4. These alternative coreceptors, particularly smCXCR6 and smGPR15, may support virus replication in SM that have restricted CCR5 expression as well as SM genetically lacking CCR5. Defining expression of these molecules on SM CD4(+) subsets may delineate distinct natural host target cell populations capable of supporting SIVsmm replication without CD4(+) T cell loss.
Asunto(s)
Cercocebus atys/genética , Clonación Molecular , Receptores CCR5/metabolismo , Receptores del VIH/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/genética , Virus de la Inmunodeficiencia de los Simios/fisiología , Internalización del Virus , Secuencia de Aminoácidos , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Línea Celular , Cercocebus atys/metabolismo , Cercocebus atys/virología , Humanos , Datos de Secuencia Molecular , Receptores CCR5/química , Receptores CCR5/genética , Receptores del VIH/química , Receptores del VIH/metabolismo , Alineación de Secuencia , Síndrome de Inmunodeficiencia Adquirida del Simio/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Replicación ViralAsunto(s)
Síndrome de Inmunodeficiencia Adquirida/inmunología , Cercocebus atys/inmunología , Resistencia a la Enfermedad/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Proliferación Celular , Cercocebus atys/virología , Humanos , Macaca mulatta/inmunología , Macaca mulatta/virología , Receptores CCR5/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/metabolismo , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Especificidad de la EspecieRESUMEN
Mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) occurs in utero, intrapartum, and through breastfeeding, with a cumulative rate of transmission of 35 to 40%. As a result, â¼ 400,000 children become infected each year. Little is known about mother-to-infant transmission (MTIT) during natural simian immunodeficiency virus (SIV) infection of sooty mangabeys (SMs) that typically is nonpathogenic despite high viral loads. In this study, we retrospectively investigated the rates of MTIT in a large colony of naturally SIV-infected SMs using serological (anti-SIV antibody by enzyme-linked immunosorbent assay [ELISA] and Western blot analysis) and virological (SIV(smm) real-time reverse transcription-PCR) methods. We examined 161 SM infants born to SIV-infected mothers and found that 150 (93.2%) were infected by non-MTIT (n = 120) or remained uninfected (n = 30). The remaining 11 SM infants (6.8%) were defined as acquiring SIV by presumptive MTIT based on (i) the presence of anti-SIV antibodies without seroreversion and (ii) a viral load of >500 copies/ml of serum in the first year of life. SM infants infected with SIV by presumptive MTIT did not show any increased morbidity or mortality, indicating that the infection is nonpathogenic even when acquired early in life. Interestingly, viral loads of SIV-infected SM infants with presumptive MTIT were 2-log lower than those of SIV-infected adult SMs living in the same colony (i.e., â¼ 1,000 and 100,000 copies/ml, respectively). These results indicate that MTIT is substantially less frequent in naturally SIV-infected SMs than in HIV-1-infected humans and results in nonpathogenic infection associated with low SIV viremia. Evolutionary pressure to reduce MTIT may have contributed to the restriction of SIV pathogenesis in natural hosts.
Asunto(s)
Cercocebus atys/virología , Transmisión Vertical de Enfermedad Infecciosa/veterinaria , Enfermedades de los Monos/transmisión , Síndrome de Inmunodeficiencia Adquirida del Simio/transmisión , Virus de la Inmunodeficiencia de los Simios/fisiología , Viremia/virología , Animales , Animales Recién Nacidos/virología , Femenino , Masculino , Enfermedades de los Monos/inmunología , Enfermedades de los Monos/mortalidad , Enfermedades de los Monos/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/mortalidad , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/inmunología , Tasa de Supervivencia , Carga Viral , Viremia/inmunología , Viremia/mortalidad , Viremia/transmisiónRESUMEN
The development of an HIV-1 vaccine that would be effective against all existing subtypes and circulating recombinant forms remains one of the great scientific and public health challenges of our generation. One of the major barriers to HIV-1 vaccine development is a lack of understanding of the correlates of protective immunity against the virus. In this context, research has focused on the rare phenomenon of spontaneous control of HIV-1 infection, in groups referred to as 'long-term nonprogressors' and 'elite controllers', together with models of nonprogressive sooty mangabey simian immunodeficiency (SIV) infection in African nonhuman primate hosts such as sooty mangabeys and African green monkeys, in which the majority of animals tolerate high levels of viral replication without development of immunodeficiency or disease. Much less attention has been given to humans infected with the nonpandemic strain HIV-2, derived from the SIV in West Africa, most of whom behave as long-term nonprogressors or viral controllers, while a minority develop disease clinically indistinguishable from AIDS caused by HIV-1. This apparent dichotomous outcome is, based on the evidence accumulated to date, more clearly related to the host immune response than the good clinical outcome of HIV-1 controllers. We propose that complementing research into HIV-1 controllers and nonpathogenic SIV models with the prioritization of HIV-2 research could enhance the HIV-1 vaccine research effort. The absence of disease progression or detectable plasma viral replication in the presence of an effective immune response in most patients living with HIV-2 represents an opportunity to unravel the virus' evolutionary adaptation in human hosts and to establish the correlates of such a protective response.
Asunto(s)
Vacunas contra el SIDA , Modelos Animales de Enfermedad , Infecciones por VIH/prevención & control , VIH-1/inmunología , VIH-2/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/fisiopatología , Sobrevivientes , Animales , Cercocebus atys/inmunología , Cercocebus atys/virología , Chlorocebus aethiops/inmunología , Chlorocebus aethiops/virología , Progresión de la Enfermedad , Infecciones por VIH/inmunología , Infecciones por VIH/fisiopatología , Infecciones por VIH/virología , VIH-1/patogenicidad , VIH-2/patogenicidad , Humanos , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/inmunología , Replicación ViralRESUMEN
Although stretches of serine and threonine are sometimes sites for O-linked carbohydrate attachment, specific sequence and structural determinants for O-linked attachment remain ill defined. The gp120 envelope protein of SIVmac239 contains a serine-threonine-rich stretch of amino acids at positions 128 to 139. Here we show that lectin protein from jackfruit seed (jacalin), which binds to non- and monosialylated core 1 O-linked carbohydrate, potently inhibited the replication of SIVmac239. Selection of a jacalin-resistant SIVmac239 variant population resulted in virus with specific substitutions within amino acids 128 to 139. Cloned simian immunodeficiency virus (SIV) variants with substitutions in the 128-to-139 region had infectivities equivalent to, or within 1 log unit of, that of SIVmac239 and were resistant to the inhibitory effects of jacalin. Characterization of the SIVmac239 gp120 O-linked glycome showed the presence of core 1 and core 2 O-linked carbohydrate; a 128-to-139-substituted variant gp120 from jacalin-resistant SIV lacked O-linked carbohydrate. Unlike that of SIVmac239, the replication of HIV-1 strain NL4-3 was resistant to inhibition by jacalin. Purified gp120s from four SIVmac and SIVsm strains bound jacalin strongly in an enzyme-linked immunosorbent assay, while nine different HIV-1 gp120s, two SIVcpz gp120s, and 128-to-139-substituted SIVmac239 gp120 did not bind jacalin. The ability or inability to bind jacalin thus correlated with the presence of the serine-threonine-rich stretch in the SIVmac and SIVsm gp120s and the absence of such stretches in the SIVcpz and HIV-1 gp120s. Consistent with sequence predictions, two HIV-2 gp120s bound jacalin, while one did not. These data demonstrate the presence of non- and monosialylated core 1 O-linked carbohydrate on the gp120s of SIVmac and SIVsm and the lack of these modifications on HIV-1 and SIVcpz gp120s.