RESUMEN
Human immunodeficiency virus type 1 (HIV-1) genetic diversity is a major obstacle for the design of a successful vaccine. Certain viral polymorphisms encode human leukocyte antigen (HLA)-associated immune escape, potentially overcoming limited vaccine protection. Although transmission of immune escape variants has been reported, the overall extent to which this phenomenon occurs in populations and the degree to which it contributes to HIV-1 viral evolution are unknown. Selection on the HIV-1 env gene at transmission favors neutralization-sensitive variants, but it is not known to what degree selection acts on the internal HIV-1 proteins to restrict or enhance the transmission of immune escape variants. Studies have suggested that HLA class I may determine susceptibility to HIV-1 infection, but a definitive role for HLA at transmission remains unproven. Comparing populations of acute seroconverters and chronically infected patients, we found no evidence of selection acting to restrict transmission of HIV-1 variants. We found that statistical associations previously reported in chronic infection between viral polymorphisms and HLA class I alleles are not present in acute infection, suggesting that the majority of viral polymorphisms in these patients are the result of transmission rather than de novo adaptation. Using four episodes of HIV-1 transmission in which the donors and recipients were both sampled very close to the time of infection we found that, despite a transmission bottleneck, genetic variants of HIV-1 infection are transmitted in a frequency-dependent manner. As HIV-1 infections are seeded by unique donor-adapted viral variants, each episode is a highly individual antigenic challenge. Host-specific, idiosyncratic HIV-1 antigenic diversity will seriously tax the efficacy of immunization based on consensus sequences.
Asunto(s)
Productos del Gen env/genética , Seropositividad para VIH/genética , Seropositividad para VIH/transmisión , VIH-1/genética , Polimorfismo Genético , Vacunas contra el SIDA/genética , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/uso terapéutico , Enfermedad Aguda , Adaptación Fisiológica/genética , Adaptación Fisiológica/inmunología , Adulto , Enfermedad Crónica , Evolución Molecular , Productos del Gen env/inmunología , Genes MHC Clase I/genética , Genes MHC Clase I/inmunología , Seropositividad para VIH/inmunología , Seropositividad para VIH/terapia , VIH-1/inmunología , Antígenos HLA/genética , Antígenos HLA/inmunología , Humanos , Inmunoterapia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Selección GenéticaRESUMEN
Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.
Asunto(s)
Evolución Molecular , Infecciones por VIH/virología , VIH-1/fisiología , Mutación , Linfocitos T Citotóxicos/inmunología , Adulto , Secuencia de Aminoácidos , Niño , Epítopos , Femenino , Variación Genética , Infecciones por VIH/inmunología , Infecciones por VIH/transmisión , VIH-1/genética , VIH-1/inmunología , Antígenos HLA-B/genética , Antígenos HLA-B/inmunología , Humanos , Transmisión Vertical de Enfermedad Infecciosa , Funciones de Verosimilitud , Filogenia , Selección Genética , Linfocitos T Citotóxicos/metabolismo , Carga ViralRESUMEN
Advances in antiviral therapy have dramatically shifted the demographics of pediatric human immunodeficiency virus type 1 (HIV-1) infection in the developed world, and a growing proportion of perinatally HIV-1-infected children are now entering their second or even third decade of life. Although cellular immune responses to HIV are known to be weak in early infancy, the magnitude, breadth, and specificity of responses later in childhood have not been characterized in detail. We performed a comprehensive characterization of HIV-1-specific CD8 responses in 18 perinatally infected children (age range, 6 to 17 years), most of whom were on antiviral therapy, using both previously defined HIV-1 epitopes and overlapping peptides spanning all HIV-1 proteins. Multispecific responses were detected in all subjects and accounted for a median of 0.25 to 0.3% of all peripheral blood mononuclear cells that was similar to the magnitude seen in HIV-infected adults. CD8 responses were broadly directed at an average of 11 epitopes (range, 2 to 27 epitopes) and targeted nearly all HIV-1 proteins, with the highest proportion in Gag. Responses were readily detected even in those children with suppressed viremia on highly active antiretroviral therapy, although the breadth (P = 0.037) and the magnitude (P = 0.021) were significantly lower in these subjects. Each child recognized only a small minority of the HIV-1 optimal epitopes defined for his or her class I HLA alleles. Together, these data indicate that perinatally infected children who survive infancy mount a robust HIV-1-specific CD8 response that is much stronger than previously thought and is comparable in magnitude and breadth to that of adults. Moreover, this response has the potential to be broadened to target more epitopes, making these children attractive candidates for immunotherapeutic interventions.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , Transmisión Vertical de Enfermedad Infecciosa , Adolescente , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Cartilla de ADN , Epítopos/química , Epítopos/inmunología , Femenino , Infecciones por VIH/transmisión , VIH-1/inmunología , VIH-1/aislamiento & purificación , Humanos , Masculino , Datos de Secuencia Molecular , Viremia/inmunologíaRESUMEN
The value of computed tomography in the assessment of subdiaphragmatic spread was studied prospectively in 72 patients with so far untreated, histologically confirmed Hodgkin's disease. In 17 patients (23.6%) computed tomography (CT) diagnosed subdiaphragmatic involvement, with no false-positive results. In 55 (76.4%) CT was within normal limits. In 30 patients exploratory laparotomy gave false-negative results in 7 (23.4%). The causes of false-negative results in CT are that lymph-nodes which were not enlarged but involved were not demonstrated and spleen involvement was not identified. Including those correctly positively diagnosed cases (17), CT had a sensitivity of 70.8% and a false-negative rate of 29.2%. It is concluded that when CT is within normal limits only exploratory laparotomy can with certainty exclude subdiaphragmatic involvement.
Asunto(s)
Enfermedad de Hodgkin/diagnóstico por imagen , Errores Diagnósticos , Reacciones Falso Negativas , Reacciones Falso Positivas , Hepatomegalia/diagnóstico , Humanos , Laparotomía , Metástasis Linfática/diagnóstico por imagen , Linfografía , Estadificación de Neoplasias , Tomografía Computarizada por Rayos XRESUMEN
Nine patients with malignant, peripheral soft-tissue tumours were examined using a 0.35 T MR equipment. In 7 cases in which tumour presence was surgically verified, a definite identification as well as an exact determination of tumour extension was achieved using MR. The various tumours exhibited a particularly high degree of contrast when using a T2-weighted Spin-Echo-(SE) as well as the T1-weighted Inversion-Recovery-(IR) mode. The T1- and T2-relaxation times of the soft-tissue malignancies evaluated in this study were markedly longer than those obtained for normal tissue. In 2 patients within the collective, a definite exclusion of tumour recurrence was possible.