Gender Differences in Clinical Presentation and Outcomes of Epidemic Kaposi Sarcoma in Uganda

The incidence of Kaposi sarcoma (KS) has increased dramatically among women in sub-Saharan Africa since the onset of the HIV pandemic, but data on KS disease in women are limited. To identify gender-related differences in KS presentation and outcomes, we evaluated the clinical manifestations and response in men and women with AIDS-associated KS in Uganda.HIV-infected adults with KS attending the Infectious Diseases Institute (IDI) and Uganda Cancer Institute (UCI) in Kampala, Uganda between 2004 and 2006 were included in a retrospective cohort. Evaluation of KS presentation was based on the clinical features described at the initial KS visit. Response was evaluated as the time to "improvement", as defined by any decrease in lesion size, lesion number, or edema. The cohort consisted of 197 adults with HIV and KS: 55% (108/197) were women. At presentation, the median CD4 T-cell count was significantly lower in women (58 cells/mm(3); IQR 11-156 cells/mm(3)) than men (124 cells/mm(3); IQR 22-254 cells/mm(3)) (p = 0.02). Women were more likely than men to present with lesions of the face (OR 2.8, 95% CI, 1.4, 5.7; p = 0.005) and hard palate (OR 2.0, 95% CI, 1.1, 3.7; p = 0.02), and were less likely than men to have lower extremity lesions (OR 0.54, 95% CI, 0.3, 0.99; p = 0.05). Women were less likely than men to demonstrate clinical improvement (HR = 0.52, CI 0.31, 0.88; p = 0.01) in multivariate analysis.The clinical presentation and response of KS differs between men and women in Uganda. These data suggest that gender affects the pathophysiology of KS, which may have implications for the prevention, diagnosis, and treatment of KS in both men and women. Prospective studies are needed to identify predictors of response and evaluate efficacy of treatment in women with KS, particularly in Africa where the disease burden is greatest

New approaches to the treatment of human herpesvirus 8-associated disease.

Human herpesvirus 8 (HHV-8, also known as Kaposi sarcoma-associated herpesvirus or KSHV) is the etiologic agent of Kaposi sarcoma (KS) and primary effusion lymphoma (PEL), as well as many cases of Castleman disease. Despite significant advances in understanding the biology and natural history of these diseases, current treatment options have important limitations, and strategies to prevent their development in high-risk individuals are lacking. This article reviews the scope of HHV-8-associated disease, as well as the efficacy of current treatment options. Finally, novel approaches to treatment and prevention are described, including antiviral agents, targeted molecular therapy and a combination of these modalities

Genetic and serologic characterization of human herpesvirus type 8 (HHV -8) IN South Africa.

Human herpes virus type 8 (HHV-8) is strongly implicated as the etiological agent of Kaposi’s sarcoma (KS). The incidence of KS in South Africa is increasing in parallel with the HIV-1 epidemic. Molecular and serological prevalence of HHV-8 in HIV-1 infected individuals with and without KS was investigated. DNA fragments from ORF26 (capsid, 330BAM233) and ORF75 (tegument) regions were used to determine the prevalence of HHV-8 DNA in peripheral blood mononuclear cells (PBMC) from 429 HIV-1 infected individuals, 95 of whom had histologically confirmed KS. Of those without KS, 14 (4.2%) were PGR positive for HHV-8 DNA. In the individuals with KS, the proportion of HHV-8 DNA positive PBMC samples was 11 times higher (46/95,48%). Similarly, an immunofluorescence assay showed that 78% of KS patients had antibodies to HHV-8 compared to 16% of KS negative individuals. Among the KS group, 93% of PCRpositive samples were also HHV-8 antibody positive compared to only 66% of PCR negative samples indicating that viremia is associated with good antibody responses. Matched lymph node and PBMC samples were available for 8 patients. HHV-8 DNA was more frequently detected in the lymph node (3/8) than in the blood (1/8), suggesting that the lymph nodes are a reser / o r for HHV-8. These data confirm the association between HHV-8 and KS and suggest that there is a high background prevalence of HHV-8 infection in HIV-1 infected individuals in South Africa. The ORP 75 gene of 40 HHV-8 strains was sequenced and the phylogenetic relationships between South African and already published sequences were investigated. The majority (n=29) of strains overlapped with the published A and B subgroups and were termed A/B variants.Three strains were classified as subgroup C while 8 sequences did not cluster with any of the previously classified subgroups and were termed novel (N) group. The DNA distance of this novel group differed from the A, B and C subgroups by 4.7%, 3.8% and 4,5% respectively although within the N group there was only 0.4% variation. The addition of this group significantly increased the number of subgroup-specific polymorphisms from 17 to 47 over a 804 bp region. There was sufficient inter-subgroup genetic diversity that single strand conformational polymorphisms (SSCP) could be used to rapidly identify them. Thus, based on the analysis of the ORF75 gene, a unique HHV-8 sub-group is present in South Africa which accounts for 20% of circulating strains. Further studies are required to determine the extent of evolutionary phytogeny, distribution and pathogenic potential of this novel group

Genetic and serologic characterization of human herpesvirus type 8 HHV-8 in South Africa

A thesis submitted to Faculty of Medicine, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the Degree of Master of Science in Medicine. Johannesburg, 1999Human herpes virus type 8 ( HHv-8 ) is strongly implicated as the etiological agent of Kaposi's sarcoma ( KS ) The incidence of KS in South Africa is increasing in parallel with the HIV-! epidemic. Molecular serological prevalence of HHV-8 in HIV-1 infected individuals with and without KS was investigated. DNA fragments from ORF26 ( capsid, 330BAM 233 ) and ORF75 ( tegument ) regions were used to determine the prevalence of HHV-8 DNA in peripheral blood mononuclear cells ( PBMC ) from 429 HIV-! infected individuals,95 of whom had histologically confirmed KS.IT201

Recombinant DNA Technology 4 / Molecular Biology 4

Exam paper for second semester B.Tech. Biotechnology and Biomedical Technolog

Human herpesvirus-8 antibodies and DNA in HIV-1 infected patients in South Africa

HIV-infected individuals with high levels of IgG antibodies against human herpesvirus-8 (HHV-8) are at increased risk of developing Kaposi's sarcoma. The aim of this study was to measure the association between HHV-8 viraemia and IgG antibody responses (by immunofluorescence) in a group of 201 HIV-infected individuals attending outpatient clinics, 91 in-patients with AIDS and 87 HIV-infected patients admitted with Kaposi's sarcoma. Compared to HIV-infected outpatients, the adjusted odds ratio in relation to Kaposi's sarcoma was 15.4 (95% CI 4.4-54.2) in those with viraemia, 25.1 (95% CI 6.6-95.6) in those with a positive immunofluorescent signal and infinity (lower exact CI 33.6) in those with a high immunofluorescent signal (all P trend < 0.001). Among those without HHV-8 viraemia, 23% were IgG-positive, but only 5.5% had a high immunofluorescent signal. In those who were viraemic, 89.1% were IgG-positive, and 28.2% had a high immunofluorescent signal, suggesting viraemia is associated with high HHV-8 immunofluorescence IgG signa

Genotypic analysis at multiple loci across Kaposi's sarcoma herpesvirus (KSHV) DNA molecules:Clustering patterns, novel variants and chimerism

Background: the genomes of human Kaposi's sarcoma-associated herpesvirus (KSHV) display several levels of DNA sequence heterogeneity and subgrouping that show distinctive clustering patterns in related human populations. The four major subtype patterns for the hypervariable ORF-K1 protein correlate closely with the principal diasporas resulting from the migration of modern humans out of East Africa and suggest that KSHV is an ancient human virus that is transmitted primarily in a familial fashion with consequent very low recombination rates. However, chimeric genomes have also been detected, especially with regard to the presence of P versus M alleles of the ORF-K15 gene. Objectives: to understand further the genetic organization and evolutionary history of KSHV, especially with regard to possible new subtypes, recombinant genomes, constant region loci and clustering in particular ethnic groups or among classic versus epidemic cases in the same geographic area. Stitch, design: direct PCR DNA sequencing was carried out on the ORF-K1 and ORF-K15 genes at the extreme left and right hand sides, as well as on six other internal loci of diagnostic samples collected from 70 new KSHV-positive patients in Israel, South Korea, Sicily, Scandinavia, Brazil, Uganda, South Africa and the US. Results and conclusions: our overall results from more than 135 KSHV genomes from many different human population groups now provides evidence for seven distinct subtypes of KSHV genomes (referred to as A/P, B/P, C/P, D/P, M, N and Q). However, the two most closely related subtypes (A/P and C/P) are only differentiated at the LHS side of the genome, and the three most distantly related forms (M, N and Q) appear to exist only as small chimeric segments that are remnants from the RHS of more ancient forms of the virus. By analyzing multiple conserved loci across the B subtype genomes that predominate in sub-Saharan Africa, we can also now recognize three to four distinct B genome subgroups with varying patterns of inter and intratypic mosaicism. Analysis of classic KSHV genomes from Israel has revealed that the ORF-K1 clade referred to as Al' predominates in Ashkenazi Jewish immigrants from Russia, whereas C2 and C6 variants predominate in North African Sephardi Jews. A variety of chimeric genomes containing C2 or C3 ORF-K genes are disseminated among classic KS cases throughout Europe and Asia including Israel, Sicily, Scandinavia, South Korea, and Taiwan. Comparison of the genomes from classic versus AIDS-associated KSHV in the US indicates that it was derived originally by reactivation and spread of a subset of the endogenous viruses carried by descendants of immigrants from endemic areas of Northern and Eastern Europe, the Mediterranean and sub-Saharan Africa. (C) 2002 Elsevier Science B.V. All rights reserved