RESUMEN
OBJECTIVES: The extent to which highly active antiretroviral therapy (HAART) era cognitive disorders are due to active processes, incomplete clearance of reservoirs, or comorbidities is controversial. This study aimed to determine if immunologic and virologic factors influence cognition after first-time HAART in Thai individuals with HIV-associated dementia (HAD) and Thai individuals without HAD (non-HAD). METHODS: Variables were captured longitudinally to determine factors predictive of degree of cognitive recovery after first-time HAART. Neuropsychological data were compared to those of 230 HIV-negative Thai controls. RESULTS: HIV RNA and CD4 lymphocyte counts were not predictive of HAD cross-sectionally or degree of cognitive improvement longitudinally. In contrast, baseline and longitudinal HIV DNA isolated from monocytes correlated to cognitive performance irrespective of plasma HIV RNA and CD4 lymphocyte counts pre-HAART (p < 0.001) and at 48 weeks post HAART (p < 0.001). Levels exceeding 3.5 log(10) copies HIV DNA/10(6) monocyte at baseline distinguished all HAD and non-HAD cases (p < 0.001). At 48 weeks, monocyte HIV DNA was below the level of detection of our assay (10 copies/10(6) cells) in 15/15 non-HAD compared to only 4/12 HAD cases, despite undetectable plasma HIV RNA in 26/27 cases. Baseline monocyte HIV DNA predicted 48-week cognitive performance on a composite score, independently of concurrent monocyte HIV DNA and CD4 count (p < 0.001). CONCLUSIONS: Monocyte HIV DNA level correlates to cognitive performance before highly active antiretroviral therapy (HAART) and 48 weeks after HAART in this cohort and baseline monocyte HIV DNA may predict 48-week cognitive performance. These findings raise the possibility that short-term incomplete cognitive recovery with HAART may represent an active process related to this peripheral reservoir.
Asunto(s)
Complejo SIDA Demencia/sangre , Complejo SIDA Demencia/psicología , Terapia Antirretroviral Altamente Activa , Cognición , ADN Viral/sangre , VIH/genética , Adulto , Separación Celular , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Receptores de Lipopolisacáridos/sangre , Estudios Longitudinales , Masculino , Monocitos/metabolismo , Pruebas Neuropsicológicas , Estudios Prospectivos , TailandiaRESUMEN
HIV-associated dementia (HAD) is not firmly established in patients with circulating recombinant form (CRF) 01_AE HIV-1. In this study, we compared neuropsychological performance among 15 Thai individuals with HAD, 15 Thai individuals without HAD, and 30 HIV-negative control subjects. HIV-1 participants were highly active anti-retroviral therapy naive and matched by age, education, and CD4 count. Neuropsychological testing abnormalities were identified in most cognitive domains among HAD vs HIV-negative participants, confirming the presence of HAD in CRF01_AE.
Asunto(s)
Complejo SIDA Demencia/virología , VIH-1/clasificación , VIH-1/genética , Trastornos Mentales/virología , Enfermedades del Sistema Nervioso/virología , Recombinación Genética , Complejo SIDA Demencia/sangre , Complejo SIDA Demencia/psicología , Adulto , Cognición , Estudios de Cohortes , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To determine if aging changes the frequency, severity, or manifestations of symptomatic distal sensory polyneuropathy (SxDSPN) in patients with HIV-1. METHODS: Prospective observations of 70 older (age < or = 50) and 56 younger (age 20 to 40) patients with HIV, and a control group of 48 older non-HIV patients, were conducted utilizing neurologic examination, neuropsychological testing, lumbar puncture, laboratory, and medical history. RESULTS: The frequency of SxDSPN among older HIV patients was 50.4%, compared to 19.6% among younger HIV patients (p < 0.001). SxDSPN among control patients occurred in 4.2%, similar to the general population. Older compared to younger HIV patients demonstrated more severe symptoms (p = 0.02) and greater deficits for vibration (p < 0.01). Increasing numbers of neuropathic comorbidities among older compared to younger HIV patients were associated with increasing severity of deficits to pinprick (p = 0.003). Dementia and SxDSPN coexisted in 36% of the older HIV patients and in none of the younger HIV patients (p = 0.021). Older HIV patients with nadir CD4 < or =200 cells/mL were 4.23 times as likely to have SxDSPN than older patients with nadir CD4 >200 cells/mL (p = 0.007). Vibratory deficits excessive to pinprick deficits predicted SxDSPN among older (OR 2.83) but not younger seropositive patients (p = 0.036). CONCLUSIONS: Age > or = 50 increases the frequency of SxDSPN, and is associated with both vibratory loss as the predominant sensory deficit and increased severity of pinprick loss among symptomatic patients with neuropathic comorbidities. SxDSPN is associated with both dementia and low nadir CD4 in HIV-positive patients aged 50 and greater.
Asunto(s)
Complejo SIDA Demencia/epidemiología , Infecciones por VIH/epidemiología , Seropositividad para VIH/epidemiología , VIH-1 , Polineuropatías/epidemiología , Complejo SIDA Demencia/inmunología , Complejo SIDA Demencia/virología , Adulto , Distribución por Edad , Factores de Edad , Anciano , Envejecimiento/inmunología , Recuento de Linfocito CD4 , Estudios de Cohortes , Comorbilidad , Estudios Transversales , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Seropositividad para VIH/inmunología , Seropositividad para VIH/virología , Hawaii/epidemiología , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Polineuropatías/inmunología , Polineuropatías/virología , Prevalencia , Estudios Prospectivos , Índice de Severidad de la EnfermedadRESUMEN
An essential component of the HIV-1 life cycle involves insertion in the genome of an infected cell. The site of HIV-1 integration has the potential to disrupt a gene and perturb a normal cellular function. To begin to address whether disease pathogenesis may correlate with the site of insertion, flanking cellular sequences at these HIV integrated regions were directly amplified from peripheral blood mononuclear cells DNA from a broad range of infected individuals using an inverse polymerase chain reaction strategy. Amplified flanking regions were sequenced and examined for similarity to the nucleic acid database. In this group of analyzed samples, the HIV-1 provirus was inserted within non-coding regions throughout the genome of the infected host, in which 7/14 sites were positioned in close proximity to different Alu repetitive elements while 2/14 sites were located within intron sequences. Insertions were also detected at sites without a specific gene designation but not within short tandem repetitive sequences, telomeres or centromeric repeat regions. Altogether, it is expected that this approach will yield new information on sites of integration by HIV-1 that may be associated with the pathogenic manifestations of disease progression.
Asunto(s)
Sangre/virología , ADN Viral/análisis , Infecciones por VIH/virología , VIH-1/genética , Linfocitos/virología , Integración Viral , Secuencia de Bases , Cromosomas Humanos Par 22 , Cromosomas Humanos Par 6 , VIH-1/aislamiento & purificación , Humanos , Intrones , Datos de Secuencia Molecular , Provirus/genética , Provirus/aislamiento & purificación , Alineación de Secuencia , Análisis de Secuencia de ADNRESUMEN
We recently reported clonal human immunodeficiency virus (HIV involvement in four acquired immune deficiency syndrome (AIDS)-associated non-B-cell lymphoproliferations. In three of these cases HIV expression was localized to tumor-associated macrophages. Because one of the cases had a major component involved in angioproliferation, we speculated that some form of Kaposi's sarcoma (KS), which also has a major component of angioproliferation, might be involved clonally with HIV. The current study is an evaluation of four cases of KS and control tissues taken from four patients who died with complications of HIV disease. With use of the inverse polymerase chain reaction technique to identify clonal forms of HIV, a clonal form of HIV was found in one of four KS cases. The HIV-positive tumor was an early KS lesion of the bowel, and uninvolved bowel from the same patient showed no clonal HIV. Immunohistochemical analysis demonstrated the presence of prominent HIV-expressing macrophages that also coexpressed high levels of HIV tat, basic fibroblast growth factor, and interleukin-6. These data provide evidence for a pathogenic process termed "sequential neoplasia," wherein a clonal macrophage provides a growth factor milieu stimulating the proliferation of a responder cell population that ultimately becomes autonomous. In the current case, the macrophages expressing HIV were located adjacent to the KS tumor tissue and were found to be producing known KS growth factors. The absence of finding clonal HIV in three more advanced KS lesions suggests that the clonal macrophage may be required only for early pathogenesis and that sequential neoplastic changes occurring in the endothelial cells gave rise to autonomous KS.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Genes tat/genética , Infecciones por VIH/virología , VIH-1/genética , Neoplasias Intestinales/genética , Oncogenes/genética , Sarcoma de Kaposi/genética , Secuencia de Bases , Cartilla de ADN , Factor 2 de Crecimiento de Fibroblastos/análisis , Proteína p24 del Núcleo del VIH/análisis , Humanos , Interleucina-6/análisis , Neoplasias Intestinales/química , Intestinos/química , Macrófagos/virología , Datos de Secuencia Molecular , Sondas de Oligonucleótidos , Sarcoma de Kaposi/química , Integración Viral/genéticaRESUMEN
The majority of lymphomas in the setting of acquired, iatrogenic, or congenital immunodeficiencies are B-cell lymphoproliferations. We describe a rare T-cell lymphoma in a fulminantly ill patient infected with human immunodeficiency virus type 1 (HIV-1). The T-cell nature of the process was defined genotypically (monoclonal T-cell receptor beta-chain [CT beta] rearrangement) and phenotypically (CD45RO+, CD4+, CD5+, CD25+, CD8-, CD3- and negative for a variety of B-cell and monocyte markers). The CD4+, CD25+ (interleukin-2 receptor [IL-2R]) phenotype with production of IL-2 and IL-2R RNA is analogous to human T-lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma (ATLL); however, no HTLV-1 could be detected. Southern blot analysis did demonstrate monoclonally integrated HIV-1 within the tumor genome. Furthermore, the tumor cells were producing HIV p24 antigen as shown by immunohistochemistry. This is the first case of acquired immunodeficiency syndrome (AIDS)-associated non-Hodgkin's lymphoma in which HIV-1 infection may have played a central role in the lymphocyte transformation process.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Transformación Celular Viral , VIH-1 , Linfoma de Células T/etiología , Linfocitos T , Secuencia de Bases , Southern Blotting , Linfocitos T CD4-Positivos/patología , ADN Viral/análisis , Reordenamiento Génico de la Cadena beta de los Receptores de Antígenos de los Linfocitos T , Virus Linfotrópico T Tipo 1 Humano/genética , Humanos , Inmunofenotipificación , Interleucina-2/genética , Pulmón/patología , Ganglios Linfáticos/patología , Linfoma de Células T/genética , Linfoma de Células T/microbiología , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , ARN/metabolismo , Linfocitos T/inmunologíaAsunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Linfoma no Hodgkin/etiología , ADN de Neoplasias/genética , ADN Viral/genética , Reordenamiento Génico , Genes myc , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/inmunología , FenotipoRESUMEN
In a high proportion of Burkitt lymphomas, transcription of the c-myc gene is initiated from a cryptic promoter in the first intron, creating abnormal messenger RNA molecules in which intron sequences, normally spliced out of the nascent transcripts, persist. An antisense oligodeoxynucleotide directed against these intron sequences greatly inhibited the proliferation of Burkitt lymphoma cell lines containing the abnormal transcripts (ST486 and JD38), but not that of cell lines containing normal c-myc transcripts (KK124). Flow cytometry showed a pronounced reduction in intracellular c-myc protein levels in cell lines containing aberrant myc transcripts, but no change in other cellular proteins. Control oligonucleotide did not inhibit c-myc protein expression or growth. These experiments provide evidence that antisense oligonucleotides targeted against tumour-specific, aberrant RNA species could be effective in controlling the proliferation of tumour cells without affecting normal cells.