RESUMO
The Multicenter AIDS Cohort (MACS), initiated in 1983 at the Johns Hopkins School of Public Health, the University of Pittsburgh School of Public Health, Northwestern University School of Medicine, and the UCLA School of Public Health, continues to conduct studies and publish key papers on the natural history of untreated and treated HIV infection in 6972 men-who-have-sex-with-men. Through May 2011, 1,490,995 specimens have been collected, 86,883 person-years of data accrued and 1195 scientific papers published in international journals.
Assuntos
Síndrome da Imunodeficiência Adquirida , Estudos de Coortes , Estudos Multicêntricos como Assunto , Síndrome da Imunodeficiência Adquirida/patologia , Síndrome da Imunodeficiência Adquirida/terapia , Coleta de Dados , Homossexualidade Masculina , Humanos , Masculino , Editoração/tendências , Estados UnidosRESUMO
BACKGROUND: The clinical implications of a failure to achieve high CD4 cell counts while receiving virally suppressive highly active antiretroviral therapy (HAART) are uncertain. METHODS: We analysed data from HIV-infected men participating in the Multicenter AIDS Cohort Study (MACS) to elucidate associations between CD4 cell counts achieved during virally suppressive HAART and risks of AIDS or death. Inclusion criteria were: CD4 cell count <200 cells/microL before HAART initiation; >or=2 viral load (VL) determinations after HAART initiation; and sustained viral suppression, defined as all VL <50 HIV-1 RNA copies/mL, but allowing a single VL of 50-1000 copies/mL. RESULTS: One hundred and twenty-one men were included; median age was 42 years. After first VL <50 copies/mL, six participants had a new AIDS diagnosis and seven died. The median CD4 cell count change/year (cells/microL) after first VL <50 copies/mL was zero among patients who either developed AIDS or died vs. 39 among those who did not meet either endpoint (P=0.119). After controlling for time from HAART initiation to first VL <50 copies/mL, age at first VL <50 copies/mL, history of AIDS and antiretroviral therapy (ART) experience before HAART, the hazard ratio for AIDS or death at CD4 cell count of
Assuntos
Síndrome da Imunodeficiência Adquirida/imunologia , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/mortalidade , Adulto , Contagem de Linfócito CD4 , Infecções por HIV/imunologia , Infecções por HIV/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Carga ViralAssuntos
Negro ou Afro-Americano/genética , Progressão da Doença , Sistema do Grupo Sanguíneo Duffy/genética , Infecções por HIV/genética , HIV-1/fisiologia , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/genética , Adulto , Estudos de Coortes , Sistema do Grupo Sanguíneo Duffy/imunologia , Genótipo , Infecções por HIV/imunologia , Infecções por HIV/mortalidade , Infecções por HIV/patologia , Humanos , Masculino , Receptores de Superfície Celular/imunologiaRESUMO
Studies on human immunodeficiency virus type 1 (HIV-1) diversity are critical for understanding viral pathogenesis and the emergence of immune escape variants and for design of vaccine strategies. To investigate HIV-1 population genetics, we used single-genome sequencing to obtain pro-pol and env sequences from longitudinal samples (n = 93) from 14 acutely or recently infected patients. The first available sample after infection for 12/14 patients revealed HIV-1 populations with low genetic diversity, consistent with transmission or outgrowth of a single variant. In contrast, two patients showed high diversity and coexistence of distinct virus populations in samples collected days after a nonreactive enzyme-linked immunosorbent assay or indeterminate Western blot, consistent with transmission or outgrowth of multiple variants. Comparison of PR and RT sequences from the first sample for all patients with the consensus subgroup B sequence revealed that nearly all nonsynonymous differences were confined to identified cytotoxic T-lymphocyte (CTL) epitopes. For HLA-typed patients, mutations compared to the consensus in transmitted variants were found in epitopes that would not be recognized by the patient's major histocompatibility complex type. Reversion of transmitted mutations was rarely seen over the study interval (up to 5 years). These data indicate that acute subtype B HIV-1 infection usually results from transmission or outgrowth of single viral variants carrying mutations in CTL epitopes that were selected prior to transmission either in the donor or in a previous donor and that reversion of these mutations can be very slow. These results have important implications for vaccine strategies because they imply that some HLA alleles could be compromised in newly acquired HIV infections.
Assuntos
Infecções por HIV/virologia , HIV-1/classificação , HIV-1/genética , Polimorfismo Genético , Adulto , Substituição de Aminoácidos/genética , Epitopos de Linfócito T/genética , Evolução Molecular , Feminino , Protease de HIV/genética , Transcriptase Reversa do HIV/genética , HIV-1/isolamento & purificação , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Análise de Sequência de DNARESUMO
BACKGROUND: Recent case reports have suggested that some asymptomatic HIV-infected individuals can develop CNS disturbances despite intact immunologic functioning and long-term suppression of plasma HIV concentrations to undetectable levels. This possibility has not yet been systematically studied longitudinally. METHODS: Using longitudinal data from the Multicenter AIDS Cohort Study, we investigated neuropsychological performance in long-term asymptomatic HIV-infected men who have sex with men. Performance over a 5-year period on the Symbol Digit Modalities test and the Trail Making Tests were compared in three HIV-positive asymptomatic groups [defined as 1) highly active antiretroviral therapy (HAART) treated with undetectable viral loads (n = 83), 2) AIDS-free for more than 15 years without HAART (n = 29), and 3) absence of clinical AIDS or CD4(+) lymphocyte count below 200 cells/muL at the beginning and end of the study period (n = 233)] and in HIV-negative controls (n = 237). Data were analyzed using linear mixed models and proportional odds logistic regression modeling with generalized estimating equations. RESULTS: There was no evidence of performance differences or performance declines over the 5-year period of study in any of the three long-term asymptomatic groups as compared with the HIV-negative group in the Symbol Digit Modalities test or the Trail Making Tests. Performance decrements were, however, observed with increasing age in each of the tests administered, demonstrating that performance declines could be detected by these methods. CONCLUSIONS: Regardless of how long-term asymptomatic status was defined immunologically or virologically, neuropsychological test performances remained stable. These findings suggest that psychomotor speed is preserved over many years in HIV-infected individuals with controlled HIV viremia.
Assuntos
Infecções por HIV/psicologia , Desempenho Psicomotor , Adulto , Terapia Antirretroviral de Alta Atividade/tendências , Estudos de Coortes , Infecções por HIV/sangue , Infecções por HIV/epidemiologia , Soropositividade para HIV/sangue , Soropositividade para HIV/diagnóstico , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Desempenho Psicomotor/fisiologia , TempoRESUMO
Previous research has demonstrated isolated effects of host genetic factors on the progression of human immunodeficiency virus type 1 (HIV-1) infection. In this paper, the authors present a novel use of multivariable methods for estimating the prevented fraction of acquired immunodeficiency syndrome (AIDS) cases attributable to six restriction genes after accounting for their epidemiologic interactions. The methods presented will never yield a prevented fraction above 1. The study population consisted of a well-characterized cohort of 525 US men with HIV-1 seroconversion documented during follow-up (1984-1996). On the basis of a regression tree approach using a Cox proportional hazards model for times to clinical AIDS, the combinations of genes associated with the greatest protection, relative to the lack of a protective genotype, consisted of: 1) C-C chemokine receptor 5 (CCR5)-Delta 32 and C-C chemokine receptor 2 (CCR2)-64I (relative hazard = 0.44); 2) interleukin 10 (IL10)-+/+ in combination with CCR5-Delta 32 or CCR2-64I (relative hazard = 0.45); and 3) IL10-+/+ in combination with stromal-derived factor (SDF1)-3 'A and CCR5 promoter P1/approximately P1 (relative hazard = 0.37). Overall, 30% of potential AIDS cases were prevented by the observed combinations of restriction genes (95% confidence interval: 7, 47). However, the combined effect was confined to the first 4 years following HIV-1 seroconversion. Additional research is needed to identify AIDS restriction genes with stronger and long-lasting protection to better characterize the genetic epidemiology of HIV-1.
Assuntos
Síndrome da Imunodeficiência Adquirida/genética , HIV-1/imunologia , Síndrome da Imunodeficiência Adquirida/epidemiologia , Síndrome da Imunodeficiência Adquirida/prevenção & controle , Adulto , Métodos Epidemiológicos , Genótipo , Homossexualidade Masculina , Humanos , Masculino , Estudos Multicêntricos como Assunto , Estudos Prospectivos , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Eosinophils play a central role in asthma, but the interplay of the effects of smoking, eosinophils and asthma remains unclear. OBJECTIVE: The primary objective of our study was to investigate the extent to which smoking modifies the effect of asthma on circulating eosinophils, CD4+ and CD8+ T cell counts. METHODS: Data were collected semiannually between 1987 and 1994 from HIV-negative participants in the Multicenter AIDS Cohort Study. Asthma was defined by a questionnaire at baseline as a self-report of diagnosed asthma. A total of 1420 blood samples from 197 asthmatics and 15 822 from 1997 non-asthmatics were collected. RESULTS: Eosinophil levels were higher in asthmatics (28% of asthmatics had eosinophils >/=4% and 16% of non-asthmatics) regardless of smoking history, but smoking modified the association between eosinophils and asthma. Namely, the odds ratios for eosinophils being >/=4% in asthmatics to non-asthmatics decreased from 2.7 (95% CI: 2.0, 3.6) in never, to 2.1 (1.4, 3.1) in former, and to 1.5 (0.9, 2.3) in current smokers. Cross-sectional and longitudinal analyses coherently showed that smoking increased eosinophils in non-asthmatics, but the converse was true for asthmatics. In contrast, no differences in peripheral blood T cell counts between asthmatics and non-asthmatics were observed. CONCLUSION: Under the established link between increased eosinophils and asthma, these data indicate that smoking modified this relationship. This finding suggests that smoking plays a different immunological role in asthmatics and non-asthmatics.
Assuntos
Asma/sangue , Fumar/sangue , Adulto , Asma/imunologia , Contagem de Linfócito CD4 , Relação CD4-CD8 , Linfócitos T CD8-Positivos/imunologia , Estudos de Coortes , Eosinófilos/patologia , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fumar/imunologiaRESUMO
The association of different CD4(+) cell counts with the same disease risk in treated and untreated populations reflects the effectiveness of highly active antiretroviral therapy (HAART) in persons with human immunodeficiency virus (HIV). Clinical progression of disease following initiation of HAART was determined for 679 HIV-infected men in the Multicenter AIDS Cohort Study by means of Kaplan-Meier survival analyses. Cox proportional hazards models were used to assess the effects of markers of HIV disease, antiretroviral history, and demographic factors. Men who had been followed since January 1993 (pre-HAART) were used to identify CD4(+) levels associated with the acquired immunodeficiency syndrome (AIDS)-free time equivalent to that of men starting HAART with CD4(+) cell counts of <200 cells/microl. Within 3.5 years following HAART initiation, 11.3% of the subjects developed AIDS and 8.5% died. Determinants of AIDS were a CD4(+) cell count of <200 cells/microl at initiation (relative hazard = 2.25, 95% confidence interval: 1.13, 4.49) and age >45 years at initiation (relative hazard = 1.92, 95% confidence interval: 0.98, 3.77). An increase in CD4(+) cell count of >50 cells/microl immediately after HAART initiation also improved prognosis (relative hazard = 0.34, 95% confidence interval: 0.16, 0.71). AIDS risk in men starting HAART with CD4(+) counts of <200 cells/microl (median = 132) was similar to that of non-HAART users with CD4(+) counts of 375-475 cells/microl (median = 432). The equivalence of disease progression to that of nonusers with approximately 300 more cells per microl demonstrates that HAART users have a broader reconstitution of the immune system beyond that of observed increases in CD4(+) cell count.
Assuntos
Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , RNA Viral/sangue , Síndrome da Imunodeficiência Adquirida/epidemiologia , Síndrome da Imunodeficiência Adquirida/prevenção & controle , Adulto , Biomarcadores/sangue , Estudos de Coortes , Progressão da Doença , Intervalo Livre de Doença , Feminino , Infecções por HIV/imunologia , Infecções por HIV/mortalidade , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Razão de Chances , Análise de Sobrevida , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results. OBJECTIVE: To examine postulated associations of genetic alleles with HIV-1 disease progression. DESIGN: Meta-analysis of individual-patient data. SETTING: 19 prospective cohort studies and case-control studies from the United States, Europe, and Australia. PATIENTS: Patients with HIV-1 infection who were of European or African descent. MEASUREMENTS: Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models. RESULTS: Both the CCR5-Delta32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74; P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, -0.18 log(10) copies/mL and -0.14 log(10) copies/mL; P < 0.05 for both). Having the CCR5-Delta32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3'A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all). CONCLUSIONS: The CCR5-Delta32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3'A homozygosity carried no such protection.
Assuntos
Quimiocinas CXC/genética , Infecções por HIV/genética , HIV-1 , Receptores CCR5/genética , Receptores de Quimiocinas/genética , Síndrome da Imunodeficiência Adquirida/genética , Síndrome da Imunodeficiência Adquirida/mortalidade , Alelos , Quimiocina CXCL12 , Progressão da Doença , HIV-1/genética , Heterozigoto , Humanos , Modelos de Riscos Proporcionais , RNA/metabolismo , Receptores CCR2 , Análise de RegressãoRESUMO
The presence of clinical manifestations of HIV-1 infection is one measure of immune function failure. We examined the occurrence of clinical manifestations of HIV-1 infection, in particular fever and oral thrush, before and after the initiation of highly active antiretroviral therapy (HAART). Using data collected from 645 participants in the Multicenter AIDS Cohort Study (MACS) who used HAART, 7517 person-visits from January 1992 through March 2000 were stratified by time relative to HAART initiation (> or =1 year preinitiation, <1 year preinitiation, >1 year postinitiation, and > or =1 year postinitiation) and CD4+ T cell count (< or =100, 101-200, 201-350, and >350 cells/microl). Multivariate logistic regression was used to assess the relationship between HAART, CD4+ T cell count, and each self-reported symptom (oral hairy leukoplakia, diarrhea, fever, and oral thrush). After initiation of HAART, clinical manifestations of HIV-1 infection continued to occur and, similar to patterns seen before HAART, were more likely at lower CD4+ T cell counts than at higher (p < 0.001). Except for diarrhea, symptoms did not occur more frequently after HAART. Rather, beyond 1 year after initiation of HAART, there was less oral thrush even at the same CD4+ T cell count. These results provide evidence that increases in CD4+ T cell count due to HAART represent a reconstitution of immune function.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/imunologia , Síndrome da Imunodeficiência Adquirida/imunologia , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Candidíase Bucal/imunologia , Febre/imunologia , Imunocompetência , Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Adulto , Fármacos Anti-HIV/administração & dosagem , Antígenos de Diferenciação/análise , Antígenos de Diferenciação/imunologia , Biomarcadores/sangue , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Candidíase Bucal/epidemiologia , Candidíase Bucal/etiologia , Estudos de Coortes , Interpretação Estatística de Dados , Febre/etiologia , HIV-1 , Humanos , Linfonodos/citologia , NAD+ Nucleosidase/análise , NAD+ Nucleosidase/imunologiaRESUMO
Two methods are presented for measuring population effectiveness (i.e., reduction of disease in a population in which only some receive treatment) of antiretroviral therapy among human immunodeficiency virus (HIV)-infected men at risk for acquired immunodeficiency syndrome (AIDS) and followed between January 1, 1986, and June 30, 1999, in the Multicenter AIDS Cohort Study. Method I, requiring use of a seroincident cohort, estimates relative hazards of AIDS for persons at equal duration of infection. Method II, allowing use of a seroprevalent cohort, estimates relative hazards since the beginning of therapy eras for persons starting at equal levels of prognostic markers of disease stage (CD4 cell count and HIV type 1 RNA). The follow-up interval was divided into four calendar periods to characterize different eras of antiretroviral therapy. For method I, the relative hazards were 1.52 (95% confidence interval (CI): 0.93, 2.49), 0.91 (95% CI: 0.66, 1.26), and 0.30 (95% CI: 0.18, 0.51) for the eras of no therapy, dual nucleoside therapy, and potent combination antiretroviral therapy, respectively (monotherapy was the reference era). For method II, the corresponding relative hazards were 1.52 (95% CI: 1.10, 2.09), 1.03 (95% CI: 0.77, 1.38), and 0.31 (95% CI: 0.21, 0.45). These results extend the measurement of population effectiveness from incident to prevalent cohorts and demonstrate the ability of cohort studies to complement information provided by clinical trials.
Assuntos
Infecções por HIV/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/prevenção & controle , Fármacos Anti-HIV/uso terapêutico , Biomarcadores , Contagem de Linfócito CD4 , Estudos de Coortes , Progressão da Doença , Métodos Epidemiológicos , HIV/isolamento & purificação , Infecções por HIV/diagnóstico , Humanos , Masculino , Prognóstico , RNA Viral/análise , Fatores de Risco , Estudos Soroepidemiológicos , Resultado do TratamentoRESUMO
Longitudinal measurements of plasma HIV RNA were analyzed using novel segmented regression models for 62 men in the Multicenter AIDS Cohort Study who at enrollment in 1985 were HIV seropositive and who had stable CD4+ lymphocyte counts and no clinical disease progression for a 6-year period between 1985 and 1991. Through 1996, 20 of the men developed clinical AIDS or died (late progressors) and 42 remained asymptomatic (nonprogressors). Using segmented regression model methods, we estimated, for each individual, the time when a change in HIV RNA trajectory was most likely to have occurred. Prior to this time, late progressors and nonprogressors had stable plasma HIV RNA levels, although the mean level in late progressors was 0.42 log10 copies/ml higher than in nonprogressors (p = 0.018). Furthermore, late progressors showed significant increases in HIV RNA levels of 0.23 log10 copies/ml/year (1.7-fold increase/year). This increase in HIV RNA in the late progressors began approximately 1.1 years prior to the onset of their decline in CD4+ lymphocytes, and 4.8 years prior to the onset of AIDS. These results provide evidence that an increase in the slope of plasma levels of HIV RNA is a sign of incipient progression of HIV disease.
Assuntos
Infecções por HIV/virologia , HIV-1/crescimento & desenvolvimento , HIV-1/genética , RNA Viral/sangue , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/virologia , Antígenos CD4/imunologia , Contagem de Linfócito CD4 , Estudos de Coortes , Progressão da Doença , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , Estudos Longitudinais , Masculino , Análise de Regressão , Carga ViralRESUMO
We evaluated CD4 cell counts over a 3(1/2) year period following the initiation of potent antiretroviral therapy (ART) in the Multicenter AIDS Cohort Study. The study population included 314 HIV-infected gay men who provided CD4 cell counts for at least 2 years after the initiation of potent ART. Trends in CD4 cell counts and plasma HIV-RNA were analyzed by regression methods that incorporated the statistical dependencies of outcomes measured over time within individuals. Regardless of CD4 cell count at initiation of potent ART, CD4 cell counts increased significantly (p <.05) in the first 2 years after initiation. However, between 2 and 3(1/2) years after initiation, these counts neither increased nor decreased. The pattern of the proportion with plasma HIV-RNA <400 copies/ml was similar to CD4 cell count (i.e., increased significantly after initiation and plateau in the subsequent 1(1/2) years). The single most important predictor of the steady state CD4 cell count that was maintained between 2 and 3(1/2) years after initiation was the change in plasma HIV-RNA in the first year after initiation of potent ART.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Inibidores da Transcriptase Reversa/uso terapêutico , Estudos de Coortes , Quimioterapia Combinada , Infecções por HIV/epidemiologia , HIV-1/fisiologia , Homossexualidade , Humanos , Estudos Longitudinais , Masculino , RNA Viral/sangueRESUMO
OBJECTIVES: To evaluate prior antiretroviral therapy experience and host characteristics as determinants of immunologic and virologic response to highly active antiretroviral therapy (HAART). METHODS: We studied 397 men from the Multicenter AIDS Cohort Study (MACS) who initiated HAART between October 1995 and March 1999. CD4 cell count and HIV-1 RNA responses to HAART were measured at the first visit following HAART (short-term) and extending from the first visit to approximately 33 months after HAART (long-term). Prior antiretroviral experience was classified into three groups based on antiretroviral therapy use during the 5 years prior to HAART. Age, race and host genetic characteristics also were assessed for their effects on treatment response. RESULTS: Better short- and long-term CD4 cell and HIV-1 RNA responses were observed in the treatment-naive users. Intermittently and consistently experienced users did not significantly differ in response. Whereas race did not independently affect response, among those initiating HAART with > 400 x 10(6) CD4 cells/l, younger age and the Delta32 CCR5 genotype were associated with a better short-term CD4 cell response. There was a suggestion that having the protective CCR5 genotype also was associated with a better long-term CD4 cell response. CONCLUSION: Immunologic and virologic response to HAART was stronger in individuals who had no prior experience with the antiretroviral therapy agents subsequently included in their initial HAART regimen. Age, level of immune competence and immunogenetics appeared to play a role in the subsequent immune reconstitution following use of highly effective HIV therapy.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade , HIV-1 , Síndrome da Imunodeficiência Adquirida/genética , Síndrome da Imunodeficiência Adquirida/imunologia , Adulto , Fatores Etários , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Interpretação Estatística de Dados , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Regiões Promotoras Genéticas , Estudos Prospectivos , RNA Viral/sangue , Grupos Raciais , Receptores CCR2 , Receptores CCR5/genética , Receptores de Quimiocinas/genética , Fatores de TempoRESUMO
Genetic variations in the locus encoding the transporter associated with antigen processing, subunit 1 (TAP1), were systematically studied using samples from Caucasians, Africans, Brazilians, and compared with data from chimpanzees. PCR-amplified genomic sequences corresponding to the 11 exons were analyzed by single-strand conformation polymorphism (SSCP) and sequencing. Six nonsynonymous and 2 synonymous single nucleotide polymorphisms (SNPs) were found to be common in one ethnic group or another, and they involved codons 254 (Gly-GGC/Gly-GGT) in exon 3, 333 (Ile-ATC/Val-GTC) in exon 4, 370 (Ala-GCT/Val-GTT) in exon 5, 458 (Val-GTG/Leu-TTG) in exon 6, 518 (Val-GTC/Ile-ATC) in exon 7, 637 (Asp-GAC/Gly-GGC), 648 (Arg-CGA/Gln-CAA) and 661 (Pro-CCG/Pro-CCA) in exon 10. At each SNP site the sequence listed first was predominant in all ethnic groups. Several SNPs segregated on the same chromosome regardless of populations and species. Together, the SNPs produced 5 major human TAP1 alleles, 4 of which matched the officially recognized alleles *0101, *02011, *0301, and *0401; the 5th allele differed from each of those by at least 4 SNPs. Overall, TAP1*0101 was the predominant allele in all ethnic groups, with frequencies ranging from 0.667 in Zambians to 0.808 in US Caucasians. The TAP1*0401 frequency showed the greatest difference between Africans (0.221-0.254) and Caucasians (0.033), with Brazilians (0.058) fitting in the middle. Consistent with earlier work based on Caucasians and gorillas, *0101 appeared to be the newest human TAP1 allele, suggesting a dramatic spread of *0101 into all human populations examined. Characterization of TAP1 polymorphisms allowed the design of a PCR-based genotyping scheme that targeted 7 SNP sites and required 2 separate genotyping techniques.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Etnicidade , Evolução Molecular , Polimorfismo Conformacional de Fita Simples , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/classificação , Alelos , Animais , Genótipo , Humanos , Pan troglodytesRESUMO
BACKGROUND: It is unclear whether there are differences between men and women with human immunodeficiency virus type 1 (HIV-1) infection in the plasma level of viral RNA (the viral load). In men, the initial viral load after seroconversion predicts the likelihood of progression to the acquired immunodeficiency syndrome (AIDS), but the relation between the two has not been assessed in women. Currently, the guidelines for initiating antiretroviral therapy are applied uniformly to women and men. METHODS: From 1988 through 1998, the viral load and the CD4+ lymphocyte count were measured approximately every six months in 156 male and 46 female injection-drug users who were followed prospectively after HIV-1 seroconversion. RESULTS: The median initial viral load was 50,766 copies of HIV-1 RNA per milliliter in the men but only 15,103 copies per milliliter in the women (P<0.001). The median initial CD4+ count did not differ significantly according to sex (659 and 672 cells per cubic millimeter, respectively). HIV-1 infection progressed to AIDS in 29 men and 15 women, and the risk of progression did not differ significantly according to sex. For each increase of 1 log in the viral load (on a base 10 scale), the hazard ratio for progression to AIDS was 1.55 (95 percent confidence interval, 0.97 to 2.47) among the men and 1.43 (95 percent confidence interval, 0.76 to 2.69) among the women. The median initial viral load was 77,822 HIV-1 RNA copies per milliliter in the men in whom AIDS developed and 40,634 copies per milliliter in the men in whom it did not; the corresponding values in the women were 17,149 and 12,043 copies per milliliter. Given the recommendation that treatment should be initiated when the viral load reaches 20,000 copies per milliliter, 74 percent of the men but only 37 percent of the women in our study would have been eligible for therapy at the first visit after seroconversion (P<0.001). CONCLUSIONS: Although the initial level of HIV-1 RNA was lower in women than in men, the rates of progression to AIDS were similar. Treatment guidelines that are based on the viral load, rather than the CD4+ lymphocyte count, will lead to differences in eligibility for antiretroviral treatment according to sex.
Assuntos
Infecções por HIV/virologia , HIV-1/isolamento & purificação , RNA Viral/sangue , Carga Viral , Síndrome da Imunodeficiência Adquirida/virologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Progressão da Doença , Intervalo Livre de Doença , Definição da Elegibilidade , Feminino , Anticorpos Anti-HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/genética , HIV-1/imunologia , Humanos , Estudos Longitudinais , Masculino , Guias de Prática Clínica como Assunto , Análise de Regressão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Risco , Fatores SexuaisRESUMO
OBJECTIVES: To determine the effectiveness of potent antiretroviral therapy in reducing opportunistic infections (OI) as both a presenting event and subsequent to an AIDS-defining event. DESIGN AND METHODS: A total of 543 seroconverters and 1470 men with AIDS were compared for the time to development of OI as the presenting AIDS event and as a subsequent event in the 1984-1989, 1990-1992, 1993-1995, and 1996-1998 periods, when the major treatments were no therapy, monotherapy, combination therapy, and potent antiretroviral therapy, respectively. RESULTS: The seroconverters suffered 132 OI and the participants with AIDS had 717 OI. The relative hazard (RH) of OI as the presenting AIDS event declined by 81% in the calendar period when potent antiretroviral therapy was available compared with the monotherapy period. Declines were observed for Mycobacterium avium complex, cytomegalovirus disease, and esophageal candidiasis, but were statistically significant only for Pneumocystis carinii pneumonia. The RH of OI as a secondary infection dropped by 77% in the last calendar period compared with the monotherapy period. A significant decline was observed for all four OI. Prophylactic drug use did not increase in the era of potent antiretroviral therapy. CONCLUSION: The hazard of OI in the era of potent antiretroviral therapy has declined dramatically compared with the era of monotherapy, despite the concurrent decrease in the use of prophylactic drugs. Physicians should consider whether it is necessary to include prophylactic drugs as part of the complex drug regimen for patients on potent antiretroviral therapy.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade , Soropositividade para HIV/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Adulto , Negro ou Afro-Americano , População Negra , Candidíase Bucal/epidemiologia , Estudos de Coortes , Progressão da Doença , Humanos , Incidência , Masculino , Infecção por Mycobacterium avium-intracellulare/epidemiologia , Infecções por Pneumocystis/epidemiologia , Infecções por Pneumocystis/prevenção & controle , Prevalência , Fatores de Risco , Fatores de Tempo , Estados Unidos/epidemiologiaRESUMO
Latent infection of resting CD4(+) T cells represents a major barrier to eradication of human immunodeficiency virus type 1 (HIV-1). The establishment and rate of decay of latent HIV-1 in resting CD(+) T cells from 9 acute seroconverters, 7 of whom began to receive highly active antiretroviral therapy (HAART) shortly after presentation, were studied. Before the initiation of therapy, these patients had very high frequencies of latently infected CD4(+) T cells, with a median frequency of 205 infectious units per million resting CD4(+) T cells. These values are > or =1 log higher than those seen in chronically infected patients who are not undergoing HAART. The number of latently infected cells declined dramatically after initiation of HAART but then tended to level off at a low but stable level. The biphasic decay of latent HIV in resting CD4(+) T cells in acute seroconverters supports current models of pre- and postintegration latency.
Assuntos
Linfócitos T CD4-Positivos/virologia , Infecções por HIV/imunologia , HIV-1 , Doença Aguda , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/imunologia , Células Cultivadas , Infecções por HIV/tratamento farmacológico , Soropositividade para HIV/imunologia , HIV-1/fisiologia , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Latência ViralRESUMO
CONTEXT: HIV-1 RNA and lymphocyte subset levels are the principal indications for antiretroviral treatment. Past reports have differed with regard to the effect of gender and race on these measures and in measures of disease progression. OBJECTIVE: To assess racial and gender differences in HIV-1 RNA levels and CD4+ lymphocyte decline. DESIGN: A longitudinal study based in the two largest HIV natural history cohort studies conducted in 7 metropolitan areas of the United States. RESULTS: In all, 1256 adult women and 1603 adult men for whom multiple data points were available prior to initiation of antiretroviral therapy were included. Women were more likely to be nonwhite, to have a history of injection drug use, and to have HIV-associated symptoms. After adjustment for differences in measurement method, baseline CD4+ cell count, age, and clinical symptoms, HIV-1 RNA levels were 32% to 50% lower in women than in men at CD4+ counts >200 cells/mm3 (p <.001) but not at CD4+ cell counts <200 cells/mm3. HIV-1 RNA levels were also 41% lower in nonwhites than in whites (p <.001) and 21% lower in persons reporting a prior history of injection drug use (p <.001). Women had more rapid declines in CD4+ cell counts over time than men (difference in slope of 46 cells/year) and nonwhite individuals had slower decline in CD4 cell counts than whites (difference of 39 cells/year). CONCLUSIONS: Both race and gender influence the values of HIV-1 RNA and the rate of HIV-1 disease progression as indicated by decline in CD4 cell counts over time. These effects could provide clues regarding the factors that influence HIV-disease progression and may indicate that guidelines for therapy should be adjusted for demographic characteristics.
Assuntos
Infecções por HIV/virologia , HIV-1/isolamento & purificação , RNA Viral/análise , Síndrome da Imunodeficiência Adquirida/etnologia , Síndrome da Imunodeficiência Adquirida/virologia , Adolescente , Adulto , Negro ou Afro-Americano , Idoso , Contagem de Linfócito CD4 , Cidades , Estudos de Coortes , Feminino , Infecções por HIV/etnologia , Infecções por HIV/imunologia , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Análise Multivariada , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Abuso de Substâncias por Via Intravenosa/imunologia , Abuso de Substâncias por Via Intravenosa/virologia , Estados Unidos , População BrancaRESUMO
Latently infected resting CD4(+) T cells provide a long-term reservoir for human immunodeficiency virus type 1 (HIV-1) and are likely to represent the major barrier to virus eradication in patients on combination antiretroviral therapy. The mechanisms by which viruses enter the latent reservoir and the nature of the chemokine receptors involved have not been determined. To evaluate the phenotype of the virus in this compartment with respect to chemokine receptor utilization, full-length HIV-1 env genes were cloned from latently infected cells and assayed functionally. We demonstrate that the majority of the viruses in the latent reservoir utilize CCR5 during entry, although utilization of several other receptors, including CXCR4, was observed. No alternative coreceptors were shown to be involved in a systematic fashion. Although R5 viruses are present in the latent reservoir, CCR5 was not expressed at high levels on resting CD4(+) T cells. To understand the mechanism by which R5 viruses enter latent reservoir, the ability of an R5 virus, HIV-1 Ba-L, to infect highly purified resting CD4(+) T lymphocytes from uninfected donors was evaluated. Entry of Ba-L could be observed when virus was applied at a multiplicity approaching 1. However, infection was limited to a subset of cells expressing low levels of CCR5 and markers of immunologic memory. Naive cells could not be infected by an R5 virus even when challenged with a large inoculum. Direct cell fractionation studies showed that latent virus is present predominantly in resting memory cells but also at lower levels in resting naive cells. Taken together, these findings provide support for the hypothesis that the direct infection of naive T cells is not the major mechanism by which the latent infection of resting T cells is established.