VIH/sida y epigenética / HIV/AIDS and epigenetic

Resumen Desde 1981, el virus de la inmunodeficiencia humana ha afectado a más de 75 millones de personas en el mundo. La prevención, el diagnóstico temprano y, ante todo el empleo de la terapia antirretroviral, ha disminuido su morbimortalidad. Sin embargo, su cura y el desarrollo de una vacuna efectiva aún son objetivos no alcanzables a corto plazo. Una de las barreras para obtener su control es la persistencia crónica de los virus o sus subproductos en los denominados reservorios celulares, lo que induce un proceso inflamatorio crónico complejo que se manifiesta clínicamente como enfermedad cardiovascular, diversos tipos de cáncer, envejecimiento precoz, entre otras patologías. Los procesos intrínsecos que llevan a estos trastornos han estado siendo investigados a profundidad en los últimos años y la epigenética, definida como el estudio de las modificaciones que afectan de manera directa la expresión de los genes, pero sin cambios en la secuencia del ácido desoxirribonuncleico, puede ayudar a desentrañar estos retos. En esta revisión se analizan los mecanismos epigenéticos, como la metilación del ácido desoxirribonuncleico, las modificaciones en histonas y el ácido ribonucleico no codificante, como posibles blancos en el diagnóstico y tratamiento de la inflamación crónica y sus consecuencias clínicas asociadas al virus de inmunodeficiencia humana/sida.

Abstract Since 1981, over 75 million people have been infected with human immunodeficiency virus. The survival rate of patients with this infection has dramatically increased with the use of antiretroviral therapy, and this therapy significantly reduced the incidence of AIDS defining events. Despite recent progress, neither a cure nor a preventive vaccine against human immunodeficiency virus infection is likely to become available soon. Epigenetics is defined as the study of chemical modifications of intrinsic and extrinsic factors of the genetic code regulating gene expression. Three types of epigenetic markers have been found: DNA methylation, post-translational histone modifications, and non-coding RNA (ncRNA). In this review, we analyzed recent research about the relation between epigenetic mechanisms, the persistence of HIV in host cells, the chronic inflammatory response evoked, the cardiovascular diseases associated and premature aging in this population.

Association of NR1I2 gene polymorphisms and time of progression to AIDS

BACKGROUND The time of progression towards AIDS can vary greatly among seropositive patients, and may be associated with host genetic variation. The NR1I2 (PXR) gene, a ligand-activated transcription factor, regulates the transcription immune pathway genes and can therefore be targets of viral replication mechanisms influencing time of progression to AIDS. OBJECTIVE To verify the association of single nucleotide polymorphisms (SNPs) rs3814057, rs6785049, rs7643645, and rs2461817 in the NR1I2 (PXR) gene with progression to AIDS in HIV-1 infected patients. METHODS Blood samples were obtained from 96 HIV-1 positive individuals following informed consent. DNA was isolated and genotyped through real time polymerase chain reaction (PCR) for the presence of SNPs in the NR1I2. Questionnaires on socio-demographic features and behaviors were answered and time of progression to AIDS was estimated based on medical chart analysis. FINDINGS Patients with the GG genotype for rs7643645 were shown to be related with a more rapid disease progression when compared to GA and AA genotypes. This result was maintained by the Multivariate Cox Regression considering sex, ethnicity, and presence of HLA-B*57, HLA-B*27, and CCR5del32 polymorphisms. MAIN CONCLUSIONS Recent studies reported the expression of the nuclear receptors in T-Lymphocytes, suggesting their possible role in the immune response. In addition, nuclear receptors have been shown to inhibit the HIV replication, although no such mechanism has been thoroughly elucidated to date. This is the first time an association between NR1I2 polymorphism and time of progression to AIDS is reported and supports an apparent relationship between the gene in the immune response and identifies another genetic factor influencing AIDS progression.

Toxoplasmic encephalitis: role of Human Leucocyte Antigens/alleles associated with rapid progression to Acquired Immunodeficiency Syndrome

Abstract Background/aims The frequency of Human Leucocyte Antigens/alleles associated with rapid progression from Human Immunodeficiency Virus infection to Acquired Immunodeficiency Syndrome was evaluated in Brazilian patients with Acquired Immunodeficiency Syndrome with and without Toxoplasmic Encephalitis. Methods 114 patients with Acquired Immunodeficiency Syndrome (41 with Toxoplasmic Encephalitis, 43 with anti-Toxoplasma gondii antibodies, without Toxoplasmic Eencephalitis, and 30 without anti-Toxoplasma gondii antibodies circulating and without Toxoplasmic Encephalitis) were studied. Results Human Leucocyte Antigens/alleles associated with rapid progression to Acquired Immunodeficiency Syndrome, particularly HLA-B35, -DR3, and -DR1 allele group, were significantly less represented in patients with Toxoplasmic Encephalitis and Acquired Immunodeficiency Syndrome. Conclusion The presence of these Human Leucocyte Antigens/Alleles that predispose to Acquired Immunodeficiency Syndrome progression was associated with resistance to Toxoplasmic Encephalitis among Human Immunodeficiency Virus-1 carriers.

Malnutrición en niños colombianos con infección por VIH/SIDA / Malnutrition in Colombian children with HIV/AIDS infection

Introducción: La desnutrición (DNT) es una de las complicaciones más tempranas que se presenta en niños con infección por VIH/SIDA, asociada a su morbimortalidad. Igualmente como consecuencia de la terapia antriretroviral y otros medicamentos utilizados, se han encontrado problemas de resistencia a la insulina y obesidad. Objetivo: Determinar la prevalencia de malnutrición (MNT) en niños con infección por VIH/SIDA por carga viral de la Clínica de VIH/SIDA del Hospital Universitario del Valle de Cali, Colombia (HUV) y su posible asociación con algunos factores de riesgo. Metodología: Estudio descriptivo, observacional de corte transversal, con análisis de casos y controles, a quienes se les tomaron datos como carga viral, %CD4, peso y talla. Se categorizó la carga viral (copias/ml) en: <400, ≥400-<300000, ≥30000-<1 millón y ≥1 millón; y el %CD4 en: <15%, ≥15%-<25% y ≥25%. Se consideró DNT global (déficit P/E≥10%), DNT crónica (déficit T/E≥5%), DNT aguda (déficit P/T≥10%) y sobrepeso (exceso P/T≥10%). Resultados: Fueron incluidos 111 niños entre 0 meses y 15 años de edad, con predominio del género masculino (51,3%), con modo de transmisión vertical en 91,8%. El 58.5% tenían entre ≥400-<300000 copias/ml de carga viral; y el 59% presentaron %CD4 ≥25%. La valoración nutricional evidenció DNT global en 64%, DNT aguda en 58%, DNT crónica en 22% y sobrepeso en 18%. Hubo riesgo de 1.7, 1.5 y 2.0 veces más de presentar DNT global, aguda y crónica, respectivamente, si la carga viral era ≥400 copias/ml. Conclusión: En niños con infección por VIH/SIDA por carga viral de la Clínica Pediátrica de VIH/SIDA del HUV de Cali, Colombia, la prevalencia de MNT fue superior al 18%, con una relación positiva superior a 1.5 veces entre carga viral y los diferentes tipos de DNT.

Introduction: Undernutrition (UNT) is a complication that occurs earlier in children with HIV/AIDS associated morbidity and mortality. Also as a result of anti-retroviral therapies and other drugs used, have encountered problems of insulin resistance and obesity. Objective: To determine the prevalence of malnutrition (MNT) in children diagnosed with HIV/AIDS by viral load in the Pediatric Clinic HIV/AIDS at the Hospital Universitario del Valle in Cali, Colombia (HUV) and its possible association with certain risk factors. Methodology: A descriptive cross-sectional study, with case-control analysis, whose data were taken as viral load, CD4%, weight and height. Were categorized viral load (copies / ml): <400, ≥ 400 - <300000, ≥ 30000 - <1 million and ≥ 1 million, and the %CD4 <15%, ≥ 15% - <25% ≥ 25%. UNT is considered global (low W/A≥10%), chronic (low H/A≥5%), acute (low W/H≥10%) and overweight (excess W/H≥10%). Results: We included 111 children from 0 months to 15 years old with male predominance (51.3%), mode of transmission in 91.8%. 58.5% were aged ≥ 400 - <300,000 copies/ml viral load, and 59% had CD4% ≥25%. Nutritional assessment showed 64% global UNT, 58% acute UNT, 22% chronic UNT and 18% overweight. Risk was 1.7, 1.5 and 2.0 times the present global, acute and chronic UNT, respectively, if the viral load was ≥ 400 copies / ml. Conclusion: In children diagnosed with HIV/AIDS by viral load of Pediatric Clinic HIV/AIDS at the HUV in Cali, Colombia, the prevalence of MNT was higher than 18%, with a positive relationship more than 1.5 times between viral load and the different types of UNT.

Biologia molecular do HIV-1 e genética da resistência humana à AIDS / Molecular biology of the HIV-1 and genetics of human resistance to AIDS

A evolução da infecção pelo Vírus da Imunodeficiência Humana Tipo 1 (HIV-1) é influenciada por fatores virais e pelo hospedeiro. Os fatores virais estão relacionados ao subtipo circulante, tropismo,citopatogenicidade, antigenicidade e mutações no genótipo viral que induzem a resistência às drogas utilizadas na terapêutica atual. Neste contexto os padrões de variabilidade de seqüências genômicas do HIV-1 podem ser utilizados como marcadores genéticos para avaliar a tendência da evolução da infecção e a eficácia terapêutica. Por outro lado os fatores relacionados ao hospedeiro incluem genótipo HLA, produção de anticorpos neutralizantes e presença de mutações genéticas que dificultam a interação do vírus com a célula hospedeira. Análises genômicas podem ser úteis no sentido de avaliar presença de fenótipo que predispões à progressão da infecção. Neste trabalho, apresenta-se uma revisão dos principais marcadores genéticos relacionados ao vírus e ao hospedeiro que podem ser utilizados para avaliar a evolução da infecção.

Host and viral factors may influence the course of human immunodeficiency virus-1 (HIV-1) infection. Theviral factors are related to circulating subtype, tropism, cytopathogenicity, antigenicity, and viral genotypemutations that prompt the resistance against the drugs used in the current therapy. In this situation, thevariability patterns of HIV-1 genomic sequences can be used as genetic markers to evaluate the trend ofinfection course and the effectiveness of the treatment. On the other hand, the determining factors related tothe host include HLA genotype, manufacture of neutralizing antibodies, and the presence of genetic mutationsthat make difficult the interaction of virus with the host cell. Genomic analyses can be useful in the sense ofassuring the phenotype presence, which predisposes to the development of the infection. In this study wepresent a review of the major genetic markers related to the virus and to the host that can be applied toevaluate the course of infection.

Epidemiologia molecular do vírus da imunodeficiência humana do tipo I: métodos de inferência filogenética / Epidemiology molecular of the human immunodeficiency virus type I: approaches of inferring phylogenies

O crescimento das bases de dados moleculares referentes ao vírus da imunodeficiência humana do tipo I (HIV-1) aumentou progressivamente desde 1991. Pesquisadores do mundo inteiro têm se dedicado ao seqüenciamento de diferentes regiões do genoma do HIV visando elucidar o processo evolutivo viral. Supõe-se que este processo evolutivo esteja na base da pesquisa que determinará a produção de vacinas eficazes além de novas drogas para o combate da Aids. Neste trabalho, procuramos introduzir alguns aspectos da epidemiologia molecular do HIV-1 enfatizando a distribuição global dos seus subtipos e os métodos de inferência filogenética utilizados no estudo de sua evolução. Apresentamos, como aplicação dos métodos de inferência filogenética, um artigo intitulado (Epidemiologia Molecular do Sub-subtipo F1 do HIV-1), onde discutimos a epidemiologia molecular do sub-subtipo F1 buscando comparar as epidemias deste sub-subtipo no Brasil e na Romênia.

Distribution of HIV-1 resistance-conferring polymorphic alleles SDF-1-3'A, CCR2-64I and CCR5-Delta32 in diverse populations of Andhra Pradesh, South India.

Polymorphic allelic variants of chemokine receptors CCR2 and CCR5, as well as of stromal-derived factor-1 SDF-1, the ligand for the chemokine receptor CXCR4, are known to have protective effects against HIV-1 infection and to be involved with delay in disease progression. We have studied the DNA polymorphisms at the loci that encode these proteins in 525 healthy individuals without any history of HIV-1 infection from 11 diverse populations of Andhra Pradesh, South India. The two protective alleles SDF-1-3'A and CCR2-64I at the SDF-1 and CCR2 loci, respectively, are present in all populations studied, although their frequencies differ considerably across populations (from 17% to 35% for the SDF-1-3'A allele, and from 3% to 17% for CCR2-64I). In contrast the CCR5-Delta32 allele is observed only in three populations (Yamani, Pathan and Kamma), all in low frequencies (i.e. 1% to 3%). The mean number of mutant alleles (for the three loci together) carried by each individual varies from 0.475 (in Vizag Brahmins) to 0.959 (in Bohra Muslims). The estimated relative hazard values for the populations, computed from the three-locus genotype data, are comparable to those from Africa and Southeast Asia, where AIDS is known to be widespread.

Frequency of CCR5 promotorpolymorphism affecting the rate of progression to AIDS [59029-G/A] in Kuwait

To estimate the frequencies of 59029-G and 59029-A alleles associated with slow and rapid progression to AIDS in Kuwaitis. The DNA was extracted from 109 blood samples of healthy unrelated Kuwaitis. The 59029-G/A polymorphism was detected by the polymerase chain reaction/restriction fragment length polymorphism [PCR-RFLP] test. The amplification of a 268-bp fragment of the CCR5 gene encompassing the site of the polymorphism was followed by digestion with restriction endonuclease Bsp 1286I and sizing the DNA fragments by agarose gel electrophoresis. Among 109 individuals genotyped, 10, 44 and 55 were 59029-A/A homozygous, 59029-G/G homozygous and 59029-G/A heterozygous, respectively. The frequency of the G allele was 0.66 [95% CI: 0.59-0.72] while the frequency of the A allele was 0.34 [95% CI: 0.28-0.41]. Conclusions: The frequency of the AIDS-'protective' 59029-G allele in Kuwaitis is significantly higher than the frequency of the 'rapid-progression' 59029-A allele. Moreover, the frequency of the 59029-G allele in Kuwaitis is among the highest reported. However, the difference from the 59029-G allele frequencies of other ethnic groups in some cases is not statistically significant

Multiple isolates from Aids patients: aspects of an analysis by a genotypic marker and antimicrobial susceptibilities variations

Twenty-one Mycobacterium avium multisolates, from ten human immunodeficiency virus-infected patients, were typed by restriction fragment length polymorphism using as marker the IS1245 and characterized by minimum inhibitory concentration for nine different antibiotics. Two out of four patients harboring multisolates with different fingerprint profile, were therefore considered as having a polyclonal infection, since their isolates were taken from sterile site. This result confirms that polyclonal infection caused by M. avium occurs with a nonnegligenciable frequency. Analyzing the multisolates susceptibility profile of each patient it was observed that most of them were infected with strains having appreciably different antimicrobial susceptibility patterns, no matter what the genotypic pattern of the strains was. These results have strong implication for the treatment of the patients.

Los factores genéticos determinantes de la resistencia a la infección por VIH y del control de la progresión al SIDA: Implicaciones sobre la patogénesis y las estrategias terapéuticas para la erradicación del VIH. Una revisión

Esta revisión describe y discute los factores genéticos que al menos en parte, determinan la resistencia a la infección y que controlan el curso progresivo de la enfermedad en las personas infectadas por el virus de la inmunodeficiencia humana. Los factores genéticos podrían explicar la no progresión o la progresión lenta de la enfermedad, de una proporción de individuos infectados por VIH denominados no progresores a largo plazo. En general, este grupo permanece sin síntomas durante más de 10 años, mantiene estable sus niveles circulantes de cT CD4+ y habitualmente tiene baja carga viral. No obstante que los fenómenos de la no progresión y de la progresión rápida son aún incomprendidos, es probable que ciertos alelos de clase I y clase II del complejo principal de histocompatibilidad se asocien con un riesgo menor o mayor para desarrollar el síndrome de inmunodeficiencia adquirida...

Biología molecular del virus de la inmunodeficiencia humana y los recientes progresos en el tratamiento del SIDA / Molecular biology of HIV and recent progress in the treatment of AIDS

El virus de inmunodeficiencia humana (VIH), causante del síndrome de inmunodeficiencia adquirida (SIDA), ha constituido desde su emergencia hace 2 décadas, un enorme desafío a la investigación biomédica. Utilizando una amplia gama de recursos para interferir y evadir la respuesta inmune normal, infecta las células CD4+, ingresa a ellas a través de sus receptores de superficie, y expresa una alta frecuencia de mutación lo que le permite cambiar repetidamente sus determinantes antígenos. Los VIH tipo 1 y 2 corresponden a lentivirus, los cuales, junto a los oncornavirus y espumavirus integran la familia de retrovirus RNA humanos. En este artíulo se revisan los conocimientos actuales de la biología molecular del virus, se comentan modernas técnicas de diagnóstico como la reacción de transcriptasa reversa y polimerasa en cadena, usadas actualmente para medir la replicación del virus en la sangre del huésped infectado, y se discuten las actuales líneas de tratamiento exploradas, las que básicamente se dirigen a blancos moleculares susceptibles de intervención farmacológica que no afecten la funcionalidad celular, como son la interacción virus-receptor celular, , transcripción reversa del RNA viral, integración del provirus, procesamiento proteolítico del precursor gag-pol, y la regulación transcripcional virus específica por los productos tat y rev. Finalmente se comentan aspectos relacionados a la investigación en el campo de la inmunización VIH, desafío pendiente para la primera década de este nuevo siglo

Epidemiología molecular del virus de inmunodeficiencia humana tipo 1 en Santiago, Chile / Molecular epidemiology of the human immunodeficiency virus tipe 1 in Santiago, Chile

Background: most of the studies of HIV-1 infection in South America have been limited to Brazil and little is known about the viral variants that are causing disease else where in the continent. Aim: to determine the characteristics of the viral variants present in Chile as well as patterns of viral transmission. Material and methods: viral sequences were obtained from 21 HIV-1 infected people from Santiago, Chile who were infected either via sexual contact or intravenous drug use. Cloned sequences obtained from both the third variable and conserved regions of the envelope as well as the viral protease were evaluated. Results: we found only clade B subtype viruses in Santiago. An evaluation of the envelope gene revealed no evidence that the sequences were monophyletic by risk group. A number of the protease sequences were predicted to encode amino acid substitutions commonly found during selection for protease inhibitor resistance. Conclusions: the HIV-1 strains studied in Chile, belong to the subtype B. There is no molecular evidence of separate introductions of the virus into the different risk groups. A number of substitutions in the protease gene that may confer resistance to protease inhibitors were found in patients with no previous exposure to this class of drugs

Genetic variability of HIV-1 isolates from Minas Gerais, Brazil

We report results of nucleotide sequencing and phylogenetic analysis of the env gene of 11 HIV-1 isolates, in Belo Horizonte, Brazil. Ten isolates belonged to HIV-1 subtype B and one was a probable B/F mosaic. This putative B/F recombinant is similar but not identical in its nucleotide sequence to other B/F mosaics described in Brazil.

Epidemiology of HIV infection in the Republic of Korea

Since the first case of human immunodeficiency virus (HIV) infection in the Republic of Korea (ROK) was detected in 1985, 876 HIV-infected patients have been reported, as of December 1998. The male to female ratio was 6.8:1, and 87% of the patients were between 20 and 49 years of age. The major modes of transmission were sexual contacts, accounting for 86% of the cases (65% heterosexuals and 21% homosexuals). Transmission through blood and blood products accounted for 28 cases (3.2%), and vertical transmission for one case. No cases among intravenous drug abusers were reported. The seroprevalence among the blood donors was approximately one in 100,000. Subtypes A, B, C, D, E, and G of HIV-1 have been introduced into the ROK, and subtype B is the most predominant subtype. The frequency of the a deletion in the CCR5 gene, a coreceptor of HIV-1, was less than 1% among Koreans.

delta ccr-5 mutation in the CCR-5 chemokine receptor gene conferring resistance to human immunodeficiency virus type 1: frequency in Kuwait

The homozygous deletion of 32 nucleotides in the CCR-5 gene [delta ccr-5] confers resistance to macrophage-tropic HIV-1. The aim of this study was to determine the frequency of delta ccr-5 in populations residing in Kuwait. A polymerase chain reaction [PCR] test for delta ccr-5 has been developed. The specificity of the test has been proved by direct sequencing of the PCR products amplified from individuals homozygous for the wild-type allele and from delta ccr-5/wild-type heterozygotes. Among 353 healthy individuals residing in Kuwait [270 Kuwaiti citizens and 83 Bedouins] tested for the delta ccr-5 mutation, 8 heterozygotes have been identified, 4 in each group. No homozygotes for the delta ccr-5 deletion have been found. The frequency of the delta ccr-5 allele in Kuwaiti nationals and Bedouins residing in Kuwait is 0.74 and 2.4%, respectively. The delta ccr-5 mutation is present in populations residing in Kuwait, though its frequency is quite low and can hardly influence the pace of HIV-1 spreading in Kuwait

Avances recientes en VIH/SIDA: terapia antiretroviral / Recent advances in HIV/AIDS: antiretroviral therapy

Recent advances in our understanding of the pathogenesis of HIV infection in patients with the acquired immunodeficiency syndrome (AIDS) are leading us to explore new treatment strategies, including the use of combination antiretroviral therapy. In this review, we present information from recently completed clinical trials that explore the use of combination therapy, including ACTG 175, the Delta studies, and the NUCA studies. In addition, we present preliminary information about the use of protease inhibitors, the newest class of antiretrovirals.