RESUMEN
Both naive and memory T lymphocyte responses are lost during advanced HIV infection. Treatment with highly active antiretroviral therapy (HAART) is associated with an increase in T lymphocytes and a reduction in viral load. However, the viral response to HAART in patients with low levels of helper T lymphocytes and a high viral load is often not satisfactory. We investigated the capacity of long-term HAART to reconstitute the immune system in severely ill patients. A nonselected longitudinal patient population with high baseline viral levels and CD4(+) cells below 100 x 10(6)/liter were monitored for 2 years during HAART. Markers to estimate the therapeutic effects included viral levels and cell surface markers representing naive and memory T lymphocytes as well as activation markers, B cells, NK cells, and clinical events. After 2 years of treatment, viral load was reduced to undetectable levels in 55% (viral responders, vRs) and less than 1 log (median value) from baseline in 45% (viral low responders, vLRs). Elevated numbers of memory and naive CD4(+) and CD8(+) cells as well as a decrease in activation markers were seen in both vRs and vLRs. However, the magnitude was greater in vRs. No differences in the clinical outcome were observed between vRs and vLRs. We conclude that most patients, even in advanced stages of HIV disease, benefited from HAART. The magnitude of the response was related to good viral reduction, but even patients with poor viral reduction had a recovery of naive and memory CD4(+) and CD8(+) cells. Even a small reduction in viral load is thus of importance for health and potentially also for years of survival.
Asunto(s)
Terapia Antirretroviral Altamente Activa , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/fisiología , ARN Viral/sangre , Adulto , Linfocitos B/inmunología , Femenino , Citometría de Flujo , Infecciones por VIH/virología , Humanos , Memoria Inmunológica , Células Asesinas Naturales/inmunología , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Subgrupos de Linfocitos T/inmunología , Resultado del Tratamiento , Carga ViralAsunto(s)
Biotecnología , Industria Farmacéutica , Genoma Humano , Biblioteca Genómica , Proyecto Genoma Humano , Humanos , ARN Mensajero , InvestigaciónRESUMEN
OBJECTIVES: We evaluated whether DNA immunization with HIV-1 regulatory genes change natural killer (NK) effector cell activity. NK cells are the most important cells for the immediate host defense against virus-infected and tumor cells. We analyzed the NK activities of HIV-1-infected individuals against K562 cells (the classical assay) as well as against a CD4+ cell line with and without HIV-1 infection. CD4+ T lymphocytes are the main target cells for HIV-1 infection in vivo. Various proportions of the CD4+ T lymphocyte population carry the HIV-1 genome, produce virus and contribute to the systemic spread of HIV-1. METHODS: CD4+ cell lines were established through HTLV-1 transformation which made the cells susceptible to NK lysis. NK activity was then tested in a (51)Cr release assay. RESULTS: NK cells of asymptomatic HIV-infected individuals mediated considerable lytic activity against K562 cells as well as against the uninfected and HIV-1-infected CD4+ cell line, and so did the NK cells of HIV-1-infected patients on highly active antiretroviral treatment. CONCLUSION: DNA immunization with HIV-1-regulatory genes did not significantly change the NK effector cell activity.
Asunto(s)
Vacunas contra el SIDA/inmunología , Genes Reguladores/inmunología , Infecciones por VIH/inmunología , Células Asesinas Naturales/inmunología , Vacunación , Vacunas de ADN/inmunología , Vacunas contra el SIDA/genética , Terapia Antirretroviral Altamente Activa , Linfocitos T CD4-Positivos/inmunología , Línea Celular Transformada , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , VIH-1/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , HumanosRESUMEN
Previous studies have indicated the presence of a putative tumor suppressor gene on chromosome 13q14, commonly deleted in patients with B-cell chronic lymphocytic leukemia (B-CLL). We have previously defined a minimally deleted region of 130 kb centromeric to the marker D13S272, and constructed a PAC and cosmid contig encompassing this area. In the present study we have made a detailed restriction and transcriptional map of the region of interest. Using these tools we have screened a panel of 206 primary CLL clones and three cell lines. In five CLL cases we found limited deletions defining the region of interest to an area of no more than 10 kb. Two adjacent genes, termed Leu1 and Leu2 (leukemia-associated gene 1 and 2), were mapped to the minimally deleted region, with several patients showing deletion borders within these genes. The Leu1 and Leu2 genes show little homology to previously published genes at the nucleotide and expected translated amino acid sequence level. Mutational analysis of the Leu1 and 2 genes in 170 CLL samples revealed no small intragenic mutations or point mutations. However, in all cases of 13q14 loss examined, the first exon of both genes, which are only 300 bp apart, were deleted. We conclude that the Leu1 and Leu2 genes are strong candidates as tumor suppressor gene(s) involved in B-CLL leukemogenesis.