Polymorphisms in cytokine genes define subpopulations of HIV-1 patients who experienced immune restoration diseases
Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, Australia. AIDS
(Impact Factor: 5.55).
11/2002; 16(15):2043-7. DOI: 10.1097/00002030-200210180-00009
To further elucidate the immunopathogenesis of immune restoration diseases (IRD) in HIV patients responding to antiretroviral therapy and determine whether IRD associated with different opportunistic pathogens involve distinct immunopathological mechanisms.
DNA samples from patients with a range of IRD were typed for polymorphic loci in genes encoding immune-mediators.
PCR-restriction fragment length polymorphism assays were used to type loci in the and genes. Alleles of a microsatellite in the CD30 promoter were determined by capillary electrophoresis.
Only 8% of patients with IRD associated with a herpesvirus infection carried IL12B-3'UTR*2, compared with 42-54% of patients with other or no IRD. Patients with IRD arising from mycobacterial infection rarely carried IL6-174*C (36% versus 61-71%) and never carried TNFA-308*2 (0% versus 23-52%). TNFA-308*2 was carried by 52% of patients who experienced IRD associated with a herpesvirus infection, as several patients with exacerbations of cytomegalovirus retinitis carried this as part of a HLA-A2,B44 haplotype. Polymorphisms in and showed no distinct patterns.
Distinct cytokine-mediated mechanisms contribute to IRD initiated by herpesvirus and mycobacterial infections.
Available from: Antonia L Wadley
- "IL-12 and IL-18 influence the induction of Th1 cytokine responses. Carriage of IL12B (3' UTR)*C was more common in Caucasian HIV-positive patients without neuropathy  and without CMV retinitis experienced after commencement of ART , suggesting a protective role in both cases. "
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Animal and in vitro models of HIV-associated sensory neuropathy suggest an inflammatory etiology. Previous genetic association studies of HIV-SN have been in small Caucasian or Asian cohorts. We assessed cytokine single nucleotide polymorphisms (SNPs) in a Black Southern African cohort.
342 black HIV-positive Southern Africans were recruited. 190 individuals had HIV-associated sensory neuropathy and 152 did not. DNA samples from all participants were genotyped for cytokine SNPs identified in studies of HIV disease and/or neuropathy.
IL4-590*T associated with an increased prevalence of HIV-SN including following correction for age, height and CD4 T-cell count. No other cytokine SNPs assessed displayed an association.
We identified a novel association between IL4-590*T and HIV-SN in African HIV-positive patients which warrants further investigation.
Molecular Immunology 03/2013; 55(3-4). DOI:10.1016/j.molimm.2013.02.002 · 2.97 Impact Factor
Available from: Jacquita S Affandi
- "Polymorphisms in immune-related genes may impact the recurrence or re-emergence of CMV in HIV patients if they favor T cell activation, apoptosis, or exhaustion, promoting extremely low nadir CD4 T cell counts. In Australian Caucasian HIV patients, CMV disease has been associated with the 44.1 ancestral haplotype (HLA-A2, B44, TNFA-308*2, BAT1(intron10)*1, DR3) and carriage of IL12B3=UTR*(1) (rs3212227, A/C) . Natural killer (NK) cells play a fundamental role in controlling viral infections such as CMV. "
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ABSTRACT: Most human immunodeficiency virus (HIV) patients are seropositive for cytomegalovirus (CMV) but a smaller proportion experience end-organ disease. This observation may reflect variations in genes affecting inflammatory and natural killer cell responses. DNA samples were collected from 240 HIV-infected patients followed at the University Hospitals/Case Medical Center (Cleveland, OH) between 1993 and 2008. Seventy-eight patients (African Americans = 41, Caucasians = 37) experienced CMV disease. Genotypes were determined using allele-specific fluorescent probes or multiplex polymerase chain reaction sequence-specific primers. IL12B3'UTR*(1) and SLC11A1 D543N*(1,2) were associated with CMV disease in African American patients (p = 0.04 and p = 0.02, respectively). IL10-1082*(1,2) and LILRB1 I142T*(1) were associated with CMV disease in Caucasians (p = 0.02 and p = 0.07, respectively). DARC T-46C*(1) and CD14 C-159T*(2) were associated with low nadir CD4(+) T cell counts in African American patients (p = 0.002 and p = 0.01, respectively). Caucasian patients carrying TNFA-308*2, TNFA-1031*(2), IL2-330*(1), CCL2-2518*(2), or LILRB1 I142T*(1) had significantly lower nadir CD4(+) T cells in a bootstrapped multivariable model (p = 0.006-0.02). In general, polymorphisms associated with CMV disease and CD4(+) T cell counts were distinct in Caucasian and African American patients in the United States. The LILRB1 I142T polymorphism was associated with both CMV disease and low nadir CD4(+) T cell counts in Caucasians, but the clearest determinant of low nadir CD4(+) T cell count in African American patients was DARC T-46C.
Human immunology 12/2011; 73(2):168-74. DOI:10.1016/j.humimm.2011.11.005 · 2.14 Impact Factor
- "Rarely, termination of ART is required. Risk factors for IRIS include lower CD4 cell count, higher viral load at start of treatment, rapidity of viral load decline; bacillary and antigen load (disseminated tuberculosis) at initiation, starting highly active ART closer to starting ATT, and genetic predisposition (HLA B-44)111–113. Although the pathophysiology of IRIS is incompletely understood, it is associated with an exuberant production of cytokines, such as IFN-γ or a lack of inhibitory immune responses114. "
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ABSTRACT: Human immunodeficiency virus (HIV) associated tuberculosis (TB) remains a major global public health challenge, with an estimated 1.4 million patients worldwide. Co-infection with HIV leads to challenges in both the diagnosis and treatment of tuberculosis. Further, there has been an increase in rates of drug resistant tuberculosis, including multi-drug (MDR-TB) and extensively drug resistant TB (XDRTB), which are difficult to treat and contribute to increased mortality. Because of the poor performance of sputum smear microscopy in HIV-infected patients, newer diagnostic tests are urgently required that are not only sensitive and specific but easy to use in remote and resource-constrained settings. The treatment of co-infected patients requires antituberculosis and antiretroviral drugs to be administered concomitantly; challenges include pill burden and patient compliance, drug interactions, overlapping toxic effects, and immune reconstitution inflammatory syndrome. Also important questions about the duration and schedule of anti-TB drug regimens and timing of antiretroviral therapy remain unanswered. From a programmatic point of view, screening of all HIV-infected persons for TB and vice-versa requires good co-ordination and communication between the TB and AIDS control programmes. Linkage of co-infected patients to antiretroviral treatment centres is critical if early mortality is to be prevented. We present here an overview of existing diagnostic strategies, new tests in the pipeline and recommendations for treatment of patients with HIV-TB dual infection.
The Indian Journal of Medical Research 12/2011; 134(6):850-65. DOI:10.4103/0971-5916.92630 · 1.40 Impact Factor
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