Clinical Course Of HIV Infection Research Articles

A genetic variation in fucosyltransferase 8 accelerates HIV-1 disease progression indicating a role for N-glycan fucosylation.

Core fucosylation by fucosyltransferase 8 (FUT8) is an important posttranslational modification that impacts components of the immune system. Genetic variations in FUT8 can alter its function and could, therefore, play a role in the antiviral immune response and pathogenesis of HIV-1. This study analysed the effect of a single nucleotide polymorphism (SNP) in FUT8 on the clinical course of HIV-1 infection. The effect of SNPs in FUT8 on untreated HIV-1 disease outcome were analysed in a cohort of 304 people with HIV-1 (PWH) using survival analysis. Flow-cytometry was used to determine the effect of SNP on T-cell activation, differentiation and exhaustion/senescence. T-cell function was determined by proliferation assay and by measuring intracellular cytokine production. The effect of the SNP on HIV-1 replication was determined by in-vitro HIV-1 infections. Sensitivity of HIV-1 produced in PBMC with or without the SNP to broadly neutralizing antibodies was determined using a TZM-bl based neutralization assay. Presence of the minor allele of SNP rs4131564 was associated with accelerated disease progression. The SNP had no effect on T-cell activation and T-cell differentiation in PWH. Additionally, no differences in T-cell functionality as determined by proliferation and cytokine production was observed. HIV-1 replication and neutralization sensitivity was also unaffected by the SNP in FUT8. SNP rs4131564 in FUT8 showed a major impact on HIV-1 disease course underscoring a role for N-glycan fucosylation even though no clear effect on the immune system or HIV-1 could be determined in vitro .

The Youngbloods. Get Together. Hypercoagulation, Complement, and NET Formation in HIV/SIV Pathogenesis

Chronic, systemic T-cell immune activation and inflammation (IA/INFL) have been reported to be associated with disease progression in persons with HIV (PWH) since the inception of the AIDS pandemic. IA/INFL persist in PWH on antiretroviral therapy (ART), despite complete viral suppression and increases their susceptibility to serious non-AIDS events (SNAEs). Increased IA/INFL also occur during pathogenic SIV infections of macaques, while natural hosts of SIVs that control chronic IA/INFL do not progress to AIDS, despite having persistent high viral replication and severe acute CD4+T-cell loss. Moreover, natural hosts of SIVs do not present with SNAEs. Multiple mechanisms drive HIV-associated IA/INFL, including the virus itself, persistent gut dysfunction, coinfections (CMV, HCV, HBV), proinflammatory lipids, ART toxicity, comorbidities, and behavioral factors (diet, smoking, and alcohol). Other mechanisms could also significantly contribute to IA/INFL during HIV/SIV infection, notably, a hypercoagulable state, characterized by elevated coagulation biomarkers, including D-dimer and tissue factor, which can accurately identify patients at risk for thromboembolic events and death. Coagulation biomarkers strongly correlate with INFL and predict the risk of SNAE-induced end-organ damage. Meanwhile, the complement system is also involved in the pathogenesis of HIV comorbidities. Despite prolonged viral suppression, PWH on ART have high plasma levels of C3a. HIV/SIV infections also trigger neutrophil extracellular traps (NETs) formation that contribute to the elimination of viral particles and infected CD4+T-cells. However, as SIV infection progresses, generation of NETs can become excessive, fueling IA/INFL, destruction of multiple immune cells subsets, and microthrombotic events, contributing to further tissue damages and SNAEs. Tackling residual IA/INFL has the potential to improve the clinical course of HIV infection. Therefore, therapeutics targeting new pathways that can fuel IA/INFL such as hypercoagulation, complement activation and excessive formation of NETs might be beneficial for PWH and should be considered and evaluated.

Information technologies for collecting and processing material on clinical course of HIV infection in epidemiological assessment of risks of contact infection in foci of combined pathology. HIV infection and tuberculosis

Due to the incidence increase of tuberculosis, there is increasing need for epidemiological surveillance of concomitant pathologies among HIV-infected people. The main goal of the authors is to develop information technologies for collecting and processing material on the incidence of HIV infection and tuberculosis in assessing the risks of contamination of contacts in the foci and the effectiveness of epidemiological response. There are descriptive and evaluative epidemiological research methods, the results of clinical studies at the work. There are also presented the features of clinical aspects of concomitant pathology that affect the risk of developing tuberculosis in contact persons. The work presents optimization of use of databases and standard computer programs, which will make it possible to carry out a comprehensive epidemiological assessment of the risks of contamination of contacts in foci of HIV infection and tuberculosis, to determine belonging of the outbreak to groups of high risk of developing tuberculosis in contact, to determine a wider range of contacts and the boundaries of the outbreak.

Prevalence of non-communicable diseases among individuals with HIV infection by antiretroviral therapy status in Dar es Salaam, Tanzania.

Long-term antiretroviral therapy has modified the clinical course of HIV infection to a chronic condition associated with increased risk of developing non-communicable diseases (NCDs). Information is scant, from sub-Saharan Africa, on the prevalence of NCDs and associated factors among individuals on ART. We consecutively enrolled individuals with HIV infection who were ART naïve and those on ART for ≥5 years (LTART) attending health facilities in Dar es Salaam. Participant's blood pressure, anthropometric measurements, and fasting blood glucose were recorded. Participants with impaired fasting blood glucose underwent an oral glucose tolerance test. A venous blood sample was sent to the lab for biochemical tests. Chi-square test was used to compare proportions, Poisson regression with robust standard errors was used to determine associations between variables. Overall, 612 individuals with HIV infection were enrolled, half of whom were ART naïve. Females comprised 71.9% and 68.0% of participants in the LTART and ART naïve study arms, respectively, p = 0.290. The mean age (±SD) was 44.9 ± 12.7 years and 37.5 ± 11.8 years among LTART and ART naïve participants, respectively, p<0.001. Hypertension was documented in 25.2% in those on LTART compared to 6.9% among ART naïve subjects, p<0.001. Impaired glucose tolerance was found in 22.9% and 4.6% among LTART compared to ART naïve subjects, p<0.001. Diabetes mellitus was detected in 17.0% of those on LTART compared to 3.9% ART naïve participants, p<0.001. Hypercholesterolemia was found in 30.4% of individuals on LTART compared to 16.7% of ART naïve subjects, p<0.001, and hypertriglyceridemia was found in 16.0% of participants on LTART compared to 9.5% of ART naïve, p = 0.015. LTART use, age ≥40 years, history of smoking, and body mass index were independently associated with NCDs. Hypertension, impaired glucose tolerance, diabetes mellitus, hypercholesterolemia, and hypertriglyceridemia were associated with long-term use of antiretroviral drugs.

EPIDEMIOLOGY OF HIV INFECTION: THE REALITY OF CLINICAL PRACTICE

Objectives. This work aims to provide retrospective analysis of socio-economic, demographic and clinical features of patients with HIV infection in 5 regions of Russian Federation with high prevalence of HIV infection (Krasnoyarsk, Tomsk, Irkutsk, Ulyanovsk Region, Samara Region). Materials and methods. A study was a part of the project «Natural and Clinical Course of HIV Infection in the Russian Federation». The protocol of study included a retrospective analysis of the regional Centers for the Prevention and Control of AIDS registers and medical records of patients. Inclusion criteria was a verified diagnosis of HIV infection. Diagnosis should be made by 01/01/2015 at the latest.Results. Demographic and socio-epidemiological parameters, clinical manifestations, immunological aspects and the status of antiretroviral therapy in the studied cohort were evaluated. The results of the analytical study allowed us to present a modern profile of the HIV-infected population.Discussion. The analysis showed the prevalence of socially adapted people of working age (30–39 years), the predominance of the parenteral route of HIV infection associated with intravenous drug use in men and the activation of the sexual route of HIV infection in a cohort of women, and other features of HIV epidemiology. Results of analytical work reflect the situation of HIV infection in the Russian Federation, justifying the need for further research in this area and implementing effective prevention strategies into practice.

Antagonistic role of IL-1ß and NLRP3/IL-18 genetics in chronic HIV-1 infection

Host genetics affects both susceptibility and progression of HIV-1 infection. NLRP3 inflammasome provides a first-line defense in viral infections, and, accordingly, gain-of-function variants in NLRP3 have been associated with protection against HIV-1.Despite antiretroviral treatment (ART), HIV-infected patients continue to present systemic inflammation with a heterogeneous prognosis. As NLRP3 inflammasome is involved in several chronic diseases by amplifying “sterile” inflammation, its role in chronic phase of HIV infection has been postulated.Little is known about inflammasome genetics in HIV-infected patients and whether it may play a role in the different clinical outcomes. Therefore, we questioned whether NLRP3 inflammasome genetics could affect the clinical course of HIV-1 infection as it does in host/virus interaction.For this purpose, we analyzed selected single nucleotide polymorphisms (SNPs) in ART-treated HIV-infected patients (n = 300), in Long Term Non-Progressors/Elite Controllers and progressors (n = 133), and in HIV-infected individuals submitted to dendritic cell (DC)-based immunotherapy (n = 19).SNPs leading to increased activation of NLRP3 inflammasome are beneficial for patients, while SNPs that negatively affect NLRP3 activation or IL-18 production, detrimental. In contrast, gain-of-function variant in IL1B is also detrimental for patients, suggesting that while IL-1ß possible contributes to immune exhaustion, the axis NLRP3-inflammasome/IL-18 could act positively in chronic infection. Functional assays supported genetic results: NLRP3 variants associated with good quality HIV+ DC, and IL1B -511C > T with a poor one. Loss-of-function SNPs affect HIV+ T cells proliferation.These findings proposed for the first time that NLRP3 inflammasome, mainly through IL-18, play a protective role in chronic HIV infection.

Stem cell transplantation in strategies for curing HIV/AIDS.

HIV-1 can persist in a latent form in resting memory CD4+ cells and macrophages carrying an integrated copy of the HIV genome. Because of the presence of these stable reservoir cells, eradication by antiretroviral therapy is unlikely and in order to achieve eradication, alternative treatment options are required. Stem cell transplantation has been considered previously to effect the clinical course of HIV-infection but in practice eradication or virus control was not achievable. However, modifications of stem cell transplantation using natural or artificial resistant cell sources, combination with new techniques of gene editing or generating cytotoxic anti HIV effector cells have stimulated this field of HIV cell therapy substantially. Here, we look back on 30 years of stem cell therapy in HIV patients and discuss most recent developments in this direction.

A cluster of rapid disease progressors upon primary HIV-1 infection shared a novel variant with mutations in the p6 gag/pol and pol/vif genes

Few studies have described the etiologic factors associated with rapid AIDS onset during primary HIV-1 infection. Our molecular epidemiological study identified a cluster of individuals infected with HIV-1 variants characterized by novel mutations in the p6 and pol/vif genes during 2011 and 2013 in Osaka, Japan. Individuals positive for the novel HIV-1 variant showed rapid disease progression, suggesting a role of viral mutations in the fostering of the clinical course of HIV-1 infection.

Stage of HIV presentation at initial clinic visit following a community-based HIV testing campaign in rural Kenya.

BackgroundThe Kenyan Ministry of Health and partners implemented a community-based integrated prevention campaign (IPC) in Western Kenya in 2008. The aim of this study was to determine whether the IPC, compared to Voluntary Counselling and Testing (VCT) services, was able to identify HIV positive individuals earlier in the clinical course of HIV infection following testing.MethodsA total of 1,752 adults aged over 15 years who tested HIV positive through VCT services or the IPC, and subsequently registered at initial clinic visit between September 2008 and September 2010, were considered in the analysis. Multivariable logistic regression models were developed to assess the association of CD4 count and WHO clinical stage of HIV infection at first clinic appointment with age group, gender, marital status and HIV testing source.ResultsMale gender and marital status were independently associated with late HIV presentation (WHO clinical stage 3 or 4 or CD4 count ≤350 cells/μl) at initial clinic visit. Patients testing HIV positive during the IPC had significantly higher mean CD4 count at initial clinic visit compared to individuals who tested HIV positive via VCT services. Patients testing HIV positive during the IPC had more than two times higher odds of presenting early with CD4 count greater than 350 cells/μl (adjusted OR 2.15, 95% CI 1.28 – 3.61, p = 0.004) and presenting early with WHO clinical stage 1 or 2 of HIV infection (adjusted OR 2.39, 95% CI 1.24 – 4.60, p = 0.01) at initial clinic visit compared to individuals who tested HIV positive via VCT services.ConclusionThe community-based integrated prevention campaign identified HIV positive individuals earlier in the course of HIV infection, compared to Voluntary Counselling and Testing services. Community-based campaigns, such as the IPC, may be able to assist countries to achieve earlier testing and initiation of ART in the course of HIV infection. Improving referral mechanisms and strengthening linkages between HIV testing and treatment services remain a challenge and electronic medical record (EMR) systems may support monitoring of patients throughout the HIV care and treatment continuum.

Clinical characteristics and obstetrical principals at HIV-infected women in Saint Petersburg

Objective: to determine the clinical course of HIV infection, pregnancy and delivery in HIV-infected women. Materials and Methods: the analysis of 1483 clinical records of the HIV-infected women, who were delivered in specialized infectious and obstetric department in Clinical infectious diseases hospital named after S.P. Botkin in 2011-2013. Results: Average age of patients - 28,2 ± 1,2 years. Vast majority of women (78,5 %) knew about the diagnosis “HIV-infection” before pregnancy. The sexual way of transmission dominated (67,6 %) among patients with the detected mechanism of HIV-transmission. Full three-step ARV prevention was performed in 82,4 % (1222) cases. The average amount of patients with 4th stage of HIV infection was 49,2 % (730), thus the number of women in labor with the 4th stage of HIV infection increased from 19,4 to 55,6 % in 2011-2013. There is a high percentage of the coinfection of HIV infection and chronic viral hepatitis C or B + C (50,8 %). The most frequent complications of pregnancy and labour at the HIV-infected women are: iron deficiency anemia, chronic placentary insufficiency, eclampsy, premature discharge of amniotic fluid. Every third pregnant has a combination of these pregnancy complications. Frequency of premature birth was 23,5 %. The majority of pregnant women had vaginal labors (67,3 %) Cesarean sections were performed in 32,7 % cases. Conclusion: In St. Petersburg in 2011-2013 significantly increased the number of women with clinically significant manifestations of HIV infection on the 4th stage of secondary diseases. The most frequent clinical manifestations of 4A stage of HIV infection were fungal (candidiasis) lesion of the mucous genitals, mouth and viral (HSV) lesions of the skin and mucous membranes. The major complications of pregnancy in HIV-infected women are anemia and chronic placental insufficiency. Almost one in four pregnancies ends premature birth. Remains high percentage of cesarean sections, including those caused by infectious indications.

Impact of GB virus C viraemia on clinical outcome in HIV‐1‐infected patients: a 20‐year follow‐up study

The impact of coexisting GB virus C (GBV-C) infection on the clinical course of HIV infection remains controversial. Early data from HIV-1 infected patients attending the Hannover Medical School in 2001 suggested prognostic benefit in GBV-C viraemic patients. The aim of this study was to evaluate patterns in long-term mortality and morbidity outcomes in this cohort. The impact of the introduction of antiretroviral therapy (ART) on the perceived benefits of GBV-C viraemia was subsequently investigated. A retrospective follow-up analysis of data in this cohort was performed. GBV-C status (GBV-C RNA positive, antibodies against GBV-C envelope protein E2 or no evidence of GBV-C exposure) had been determined at enrolment, with several markers of HIV disease progression (such as viral load and CD4 cell count) being collated from 1993/1994, 2000 and 2012. These eras were chosen to reflect variations in treatment strategies within the cohort. In addition, mortality and HIV-related morbidity data were collated for all patients. Complete data were available for 156 of 197 patients (79%). In highly active antiretroviral therapy (HAART)-naïve patients, GBV-C RNA positivity conferred significant improvements in the course of HIV infection and mortality as well as lower rates of HIV-related diseases. E2 positivity alone conferred no significant advantage. With the advent of HAART, however, the benefits GBV-C RNA positivity disappeared. Although GBV-C coinfection appears to inherently improve morbidity and mortality in HIV-infected patients, modern HAART has eradicated these advantages. Evidence of synergy between GBV-C status and HAART response exists, with further studies examining the role of GBV-C in existing treatment de-escalation strategies being required.

HIV and Tuberculosis co-infection impacts T-cell activation markers but not the numbers subset of regulatory T-cells in HIV-1 infected patients.

BackgroundTuberculosis (TB) has been shown to accelerate the clinical course of HIV infection, but the mechanisms by which this occurs are not well understood. Regulatory T-cells (Tregs) are known to dampen hyperactivation of the immune cells, but it remains unclear whether hyperactivation of T-cells in HIV infection is associated with a decrease of Tregs and what the effect Mycobacterium tuberculosis (MTB) co-infection has on T-cell activation and Tregs.ObjectivesIn this study, we aim to evaluate whether active TB is associated with the increased expression of T-cell activation markers and reduced number of Treg cells in HIV-1-infected patients.MethodsThis study was conducted on 69 subjects consisting of 20 HIV-infected patients, 20 HIV and MTB co-infected patients, 19 MTB-infected patients and 10 uninfected control subjects negative for both MTB and HIV. The frequencies of T-cell activation markers (CD38 and HLA-DR) and Treg cells (CD4+CD25+CD127-) were measured by flow cytometry.ResultsSignificantly higher expression of CD38 and HLA-DR on CD4+ and CD8+ T-cells was found in MTB and HIV co-infected patients compared with HIV-infected patients. However, no significant difference in the percentage of Treg cells was reported between HIV patients with TB and those without. The study also showed a negative correlation between regulatory T-cells frequency and CD4+ T-cell counts.ConclusionThese results suggest that TB enhances the expression of peripheral T-cell activation markers during HIV infection, whilst having no impact on the percentages of Treg cells.

Correlation of partial env gene sequences with disease progression parameters in HIV-positive pregnant women from India

Ever since the beginning of the epidemic of HIV, one of the poignant aspects of HIV infection is transmission of the virus from mother to child. It is not known whether pregnancy accelerates the progression of HIV infection from a clinically asymptomatic stage to a progressive clinical phase. Present study was carried out to understand disease progression in pregnant women from India. We studied co-receptor utilization (the major determinant of HIV disease progression), N-glycosylation sites, and sequence variability. Blood samples were collected from 25 HIV sero-positive patients, eleven from the antenatal risk group (experimental group), nine from heterosexual male, and five from heterosexual female risk group (control group). Partial env gene was amplified by PCR and sequenced. BLAST search and phylogenetic analysis were used to determine the subtype. The deduced amino acid sequence of the V3 region was used to predict co-receptor, determine sequence variability and N-glycosylation site. The experimental group comprising the antenatal risk group did not exhibit any difference in terms of co-receptor, N-glycosylation, and sequence variability when compared with the control, non-pregnant group. Pregnancy does not seem to accelerate the clinical course of HIV infection. The female body during the gestation phase possibly acquires certain strategies to impede or at least alleviate the disease progression during the crucial immune-compromised pregnancy phase, which would otherwise adversely affect the mother as well as the fetus during the infection.

Genome-Wide Association Scan in HIV-1-Infected Individuals Identifying Variants Influencing Disease Course

BackgroundAIDS develops typically after 7–11 years of untreated HIV-1 infection, with extremes of very rapid disease progression (<2 years) and long-term non-progression (>15 years). To reveal additional host genetic factors that may impact on the clinical course of HIV-1 infection, we designed a genome-wide association study (GWAS) in 404 participants of the Amsterdam Cohort Studies on HIV-1 infection and AIDS.MethodsThe association of SNP genotypes with the clinical course of HIV-1 infection was tested in Cox regression survival analyses using AIDS-diagnosis and AIDS-related death as endpoints.ResultsMultiple, not previously identified SNPs, were identified to be strongly associated with disease progression after HIV-1 infection, albeit not genome-wide significant. However, three independent SNPs in the top ten associations between SNP genotypes and time between seroconversion and AIDS-diagnosis, and one from the top ten associations between SNP genotypes and time between seroconversion and AIDS-related death, had P-values smaller than 0.05 in the French Genomics of Resistance to Immunodeficiency Virus cohort on disease progression.ConclusionsOur study emphasizes that the use of different phenotypes in GWAS may be useful to unravel the full spectrum of host genetic factors that may be associated with the clinical course of HIV-1 infection.

Predictors of Visceral Leishmaniasis Relapse in HIV-Infected Patients: A Systematic Review

Background and ObjectivesVisceral leishmaniasis (VL) is a common complication in AIDS patients living in Leishmania-endemic areas. Although antiretroviral therapy has changed the clinical course of HIV infection and its associated illnesses, the prevention of VL relapses remains a challenge for the care of HIV and Leishmania co-infected patients. This work is a systematic review of previous studies that have described predictors of VL relapse in HIV-infected patients.Review MethodsWe searched the electronic databases of MEDLINE, LILACS, and the Cochrane Central Register of Controlled Trials. Studies were selected if they included HIV-infected individuals with a VL diagnosis and patient follow-up after the leishmaniasis treatment with an analysis of the clearly defined outcome of prediction of relapse.ResultsEighteen out 178 studies satisfied the specified inclusion criteria. Most patients were males between 30 and 40 years of age, and HIV transmission was primarily via intravenous drug use. Previous VL episodes were identified as risk factors for relapse in 3 studies. Two studies found that baseline CD4+ T cell count above 100 cells/mL was associated with a decreased relapse rate. The observation of an increase in CD4+ T cells at patient follow-up was associated with protection from relapse in 5 of 7 studies. Meta-analysis of all studies assessing secondary prophylaxis showed significant reduction of VL relapse rate following prophylaxis. None of the five observational studies evaluating the impact of highly active antiretroviral therapy use found a reduction in the risk of VL relapse upon patient follow-up.ConclusionSome predictors of VL relapse could be identified: a) the absence of an increase in CD4+ cells at follow-up; b) lack of secondary prophylaxis; and c) previous history of VL relapse. CD4+ counts below 100 cells/mL at the time of primary VL diagnosis may also be a predictive factor for VL relapse.

The effect of combined polymorphisms in chemokines and chemokine receptors on the clinical course of HIV-1 infection in a Brazilian population

Polymorphisms in genes that encode chemokines or their receptors can modulate susceptibility to human immunodeficiency virus (HIV) infection and disease progression. The objective of this study was to assess the frequency of polymorphisms CCR5-Δ32, CCR2-64I, CCR5-59029A and SDF1-3'A and their role in the course of HIV infection in a Southern Brazilian population. Clinical data were obtained from 249 patients for an average period of 6.4 years and genotypes were determined by standard polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism. Survival analyses were conducted for three outcomes: CD4+ T-cell counts below 200 cells/µL, acquired immune deficiency syndrome (AIDS) or death. The frequency of the polymorphisms CCR5-Δ32, CCR2-64I, CCR5-59029A and SDF1-3'A were 0.024, 0.113, 0.487 and 0.207, respectively. CCR5-Δ32 was associated with a reduction in the risk for CD4+ T-cell depletion and with an increased risk for death after AIDS diagnosis. CCR2-64I was associated with a reduction in the risk for developing AIDS. SDF1-3'A was also associated with decreased risk for AIDS, but its effect was only evident when CCR2-64I was present as well. These results highlight the possibility of using these markers as indicators for the prognosis of disease progression and provide evidence for the importance of analysing the effects of gene polymorphisms in a combined fashion.

Antiretroviral treatment 2010: progress and controversies.

Effective antiretroviral therapy (ART) changes the clinical course of HIV infection. There are 25 antiretroviral drugs approved for the treatment of HIV infection, and current antiretroviral drug regimens are highly effective, convenient, and relatively nontoxic. ART regimens should be chosen in consideration of a patient's particular clinical situation. Successful treatment is associated with durable suppression of HIV viremia over years, and consequently, ART reduces the risk of clinical progression. In fact, current models estimate that an HIV-infected individual appropriately treated with antiretroviral drugs has a life expectancy that approaches that of the general HIV-uninfected population, although some patient groups such as injection drug users do less well. Despite these advances, continued questions about ART persist: What is the optimal time to start ART? What is the best regimen to start? When is the optimal time to change ART? What is the best regimen to change to? In addition, newer antiretroviral agents are in development, both in existing classes and in new classes such as the CD4 receptor attachment inhibitors and the maturation inhibitors. Further research will help optimize current antiretroviral treatments and strategies.

Changing patterns of AIDS: impact on the indications and diagnostic yield of bone marrow biopsies

After the advent of HAART, the clinical course of HIV infection has dramatically improved. Therefore, it seems appropriate to reevaluate the performance of bone marrow biopsy (BMB) as a diagnostic tool. The aim of the present study was to compare the reasons for performing a BMB and its diagnostic yield in HIV-patients before and after HAART. A total of 165 BMB specimens obtained from HIV-infected patients receiving care at the Hospital of Universidade Federal do Rio de Janeiro in two different periods (1986-1994 and 1999-2004) were analysed. The main reason for BMB examination in the first period was fever (88%), which decreased in the second period (57%, p < 0.0001), when cytopenia (51%) was the leading reason for BMB, whereas in the first period it accounted for only 30% (p = 0.008). A definitive diagnosis (infection, granulomas or lymphomas) was obtained in 28% of patients in the first period and in 19% during the second period (p = 0.20). The diagnosis turned out as infections decreased from 16% in period 1 to 2% in period 2 (p = 0.003). Despite the the limitations in the evaluation of fever, the use of BMB must be considered on an individual basis, whenever less invasive alternatives have been exhausted, and should be complemented by a bone marrow aspiration for microbiological studies.

Association of HLA-C and HCP5 gene regions with the clinical course of HIV-1 infection

Association of HLA-C and HCP5 gene regions with the clinical course of HIV-1 infection

X Chromosomal Variation Is Associated with Slow Progression to AIDS in HIV-1-Infected Women

AIDS has changed from a mostly male-specific health problem to one that predominantly affects females. Although sex differences in HIV-1 susceptibility are beyond doubt, the extent to which sex affects the onset and progression of AIDS has remained elusive. Here, we provide evidence for an influence of X chromosomal variation on the course of retroviral infection, both in HIV-1-infected patients and in the rhesus macaque model of AIDS. A two-stage, microsatellite-based GWAS of SIV-infected monkeys revealed MHC class I markers and a hitherto-unknown X chromosomal locus as being associated with a nominal score measuring progression to AIDS (Fisher's exact p < 10(-6)). The X chromosomal association was subsequently confirmed in HIV-1-infected patients with published SNP genotype data. SNP rs5968255, located at human Xq21.1 in a conserved sequence element near the RPS6KA6 and CYLC1 genes, was identified as a significant genetic determinant of disease progression in females (ANOVA p = 8.8 x 10(-5)), but not in males (p = 0.19). Heterozygous female carriers of the C allele showed significantly slower CD4 cell decline and a lower viral load at set point than TT homozygous females and than males. Inspection of HapMap revealed that the CT genotype is significantly more frequent among Asians than among Europeans or Africans. Our results suggest that, in addition to the individual innate and adaptive immunity status, sex-linked genetic variation impacts upon the rate of progression to AIDS. Elucidating the mechanisms underlying this sex-specific effect will promote the development of antiretroviral therapies with high efficacy in both sexes.