Denise Whitby

Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium

BACKGROUND Common genetic variants in immune and inflammatory response genes can affect the risk of developing non-Hodgkin lymphoma. We aimed to test this hypothesis using previously unpublished data from eight European, Canadian, and US case-control studies of the International Lymphoma Epidemiology Consortium (InterLymph). METHODS We selected 12 single-nucleotide polymorphisms for analysis, on the basis of previous functional or association data, in nine genes that have important roles in lymphoid development, Th1/Th2 balance, and proinflammatory or anti-inflammatory pathways (IL1A, IL1RN, IL1B, IL2, IL6, IL10, TNF, LTA, and CARD15). Genotype data for one or more single-nucleotide polymorphisms were available for 3586 cases of non-Hodgkin lymphoma and for 4018 controls, and were assessed in a pooled analysis by use of a random-effects logistic regression model. FINDINGS The tumour necrosis factor (TNF) -308G-->A polymorphism was associated with increased risk of non-Hodgkin lymphoma (p for trend=0.005), particularly for diffuse large B-cell lymphoma, the main histological subtype (odds ratio 1.29 [95% CI 1.10-1.51] for GA and 1.65 [1.16-2.34] for AA, p for trend <0.0001), but not for follicular lymphoma. The interleukin 10 (IL10) -3575T-->A polymorphism was also associated with increased risk of non-Hodgkin lymphoma (p for trend=0.02), again particularly for diffuse large B-cell lymphoma (p for trend=0.006). For individuals homozygous for the TNF -308A allele and carrying at least one IL10 -3575A allele, risk of diffuse large B-cell lymphoma doubled (2.13 [1.37-3.32], p=0.00083). INTERPRETATION Common polymorphisms in TNF and IL10, key cytokines for the inflammatory response and Th1/Th2 balance, could be susceptibility loci for non-Hodgkin lymphoma. Moreover, our results underscore the importance of consortia for investigating the genetic basis of chronic diseases like cancer.

Kaposi's-sarcoma-associated herpesvirus in HIV-negative Kaposi's sarcoma

events involving, to various degrees, microorganisms such as herpesviruses, hepatitis B virus, HIV, and Mycoplasma penetrans.H Chang and colleagues5 have identified herpesvirus-like DNA sequence in biopsy samples from patients with AIDS-associated KS. This DNA sequence was found exclusively in KS biopsy specimens but not in several other tested tissues. We report our results of screening DNA samples from isolated peripheral blood mononuclear cells (PBMCs). DNA was directly purified from uncultured PBMCs that

Activity of Thalidomide in AIDS-Related Kaposi’s Sarcoma

PURPOSE To assess the toxicity and activity of oral thalidomide in Kaposis sarcoma (KS) in a phase II dose-escalation study. PATIENTS AND METHODS Human immunodeficiency virus (HIV)-seropositive patients with biopsy-confirmed KS that progressed over the 2 months before enrollment received an initial dose of 200 mg/d of oral thalidomide in a phase II study. The dose was increased to a maximum of 1,000 mg/d for up to 1 year. Anti-HIV therapy was maintained during the study period. Toxicity, tumor response, immunologic and angiogenic factors, and virologic parameters were assessed. RESULTS Twenty patients aged 29 to 49 years with a median CD4 count of 246 cells/mm(3) (range, 14 to 646 cells/mm(3)) were enrolled. All patients were assessable for toxicity, and 17 for response. Drowsiness in nine and depression in seven patients were the most frequent toxicities observed. Eight (47%; 95% confidence interval [CI], 23% to 72%) of the 17 assessable patients achieved a partial response, and an additional two patients had stable disease. Based on all 20 patients treated, the response rate was 40% (95% CI, 19% to 64%). The median thalidomide dose at the time of response was 500 mg/d (range, 400 to 1,000 mg/d). The median duration of drug treatment was 6.3 months, and the median time to progression was 7.3 months. CONCLUSION Oral thalidomide was tolerated in this population at doses up to 1,000 mg/d for as long as 12 months and was found to induce clinically meaningful anti-KS responses in a sizable subset of the patients. Additional studies of this agent in KS are warranted.

Interassay Correlation of Human Herpesvirus 8 Serologic Tests

To standardize human herpesvirus 8 (HHV-8) antibody assays for application to asymptomatic infection, a blinded comparison was done of seven immunofluorescence assays and ELISAs. Five experienced laboratories tested a serum panel from 143 subjects in 4 diagnostic groups. Except for a minor capsid protein ELISA, the other six tests detected HHV-8 antibodies most frequently in classic (80%-100%) and AIDS-related (67%-91%) Kaposis sarcoma, followed by human immunodeficiency virus-seropositive patients (27%-60%), and least frequently in healthy blood donors (0-29%). However, these six assays frequently disagreed on individual sera, particularly for blood donor samples. Current HHV-8 antibody tests have uncertain accuracy in asymptomatic HHV-8 infection and may require correlation with viral protein or nucleic acid detection. Antibody assays are useful for epidemiologic investigations, but the absolute prevalence of HHV-8 infection in the United States cannot yet be determined.

Human immunodeficiency virus infection of monocytic and T-lymphocytic cells: Receptor modulation and differentiation induced by phorbol ester

The monocytic leukemic cell line U937 can be infected with human immunodeficiency virus type 1 (HIV-1) to become permanently infected virus producers. Uninfected U937 cells express T4 (CD4) antigen and form syncytia when mixed with HIV-1 producing cells. Anti-T4 monoclonal antibodies block syncytium formation indicating that the HIV-1 receptors on U937 cells include T4 antigen. The promyelocytic leukemic cell line HL60, while expressing only low amounts of surface T4 and not forming syncytia on exposure to HIV-1, can be infected by HIV-1 at lower efficiency than U937 and T-cell lines. 12-O-Tetradecanoylphorbol-13-acetate (TPA) treatment induces the differentiation of U937 cells into macrophages. HIV-infected U937 cells retain the ability to differentiate, though less efficiently, as shown by the appearance of monocyte/macrophage surface markers. T4 antigen on both U937 and T-cell lines is down regulated by TPA treatment. Functional receptors for HIV-1, assayed by syncytium induction and pseudotype plating, are lost concomitantly with T4 antigen following TPA treatment of U937 cells and T cells.

Update on KSHV epidemiology, Kaposi Sarcoma pathogenesis, and treatment of Kaposi Sarcoma.

Much has been learned since the discovery of KSHV in 1994 about its epidemiology and pathology but much of what has been learned has yet to be translated into clinical practice. In this review, we survey the current state of knowledge on KSHV epidemiology and KS pathogenesis and highlight therapeutic opportunities in both the developed and developing world.

Serologic Evidence of Human Herpesvirus 8 Transmission by Homosexual but Not Heterosexual Sex

Epidemiologic studies link Kaposis sarcoma with a sexually transmitted agent. Human herpesvirus 8 (HHV-8) is likely to be that agent, but routes of transmission are poorly described. A seroepidemiologic study was conducted to determine whether HHV-8 is transmitted sexually between heterosexuals. Sera from 2718 patients attending a sexually transmitted disease (STD) clinic were tested for antibodies to HHV-8 and herpes simplex virus type 2 (HSV-2). Information on sex partners in the previous 12 months and past STDs were obtained by questionnaire. Relationships between possible risk factors and HHV-8 infection were assessed by logistic regression. Overall, seroprevalence of HHV-8 was 7.3%. Independent risk factors for HHV-8 in the whole group were homo/bisexuality and birth in Africa and, among homo/bisexual men, a history of syphilis and HSV-2 and human immunodeficiency virus seropositivity. Among heterosexuals there was no evidence for sexual transmission; the only independent risk factor for HHV-8 seropositivity was birth in Africa.

Human herpesvirus 8 infection within families in rural Tanzania

Human herpesvirus 8 (HHV-8) infection is common in Africa. We examined the distribution of HHV-8 within families in rural Tanzania to determine routes of spread. HHV-8 infection was assessed by measuring antibody reactivity with a K8.1 (lytic-phase antigen) immunoassay. The prevalence increased from 3.7% (1/27) among infants to 58.1% (36/62) among children aged 3-4 years and 89.0% (65/73) among adults aged > or =45 years. Women with HHV-8-seropositive husbands had a 7-fold risk for infection (odds ratio [OR], 6.9; 95% confidence interval [CI], 1.9-25.3). HHV-8 seropositivity in children was associated with having at least 1 seropositive first-degree relative (OR, 14.7; 95% CI, 5.9-43.1), a seropositive mother (OR, 7.4; 95% CI, 3.2-16.8), a seropositive father (OR, 4.8; 95% CI, 2.3-10.1), or a seropositive next-older sibling (OR, 4.2; 95% CI, 1.9-9.4). Our data are consistent with the occurrence of HHV-8 transmission within families, from mothers and other relatives to children via nonsexual routes and between spouses via sexual routes.

An Interleukin-6-Related Systemic Inflammatory Syndrome in Patients Co-Infected with Kaposi Sarcoma-Associated Herpesvirus and HIV but without Multicentric Castleman Disease

BACKGROUND Kaposi sarcoma-associated herpesvirus (KSHV) is the causal agent for Kaposi sarcoma (KS) and multicentric Castleman disease (MCD) in human immunodeficiency virus (HIV)-infected patients. Patients with KSHV-MCD develop fevers, wasting, hypoalbuminemia, cytopenias, and hyponatremia that are related to overproduction of KSHV-encoded viral interleukin (IL)-6 (vIL-6) and human IL-6 (hIL-6). METHODS We identified 6 HIV-infected patients with KS or serological evidence of KSHV infection who had severe inflammatory MCD-like symptoms but in whom we could not diagnose MCD, and we hypothesized that these symptoms resulted from vIL-6 overproduction. Serum vIL-6 levels were assessed in these 6 patients and compared with levels in 8 control patients with symptomatic KSHV-MCD and 32 control patients with KS. KSHV viral load, serum hIL-6 level, and human IL-10 level were also evaluated. RESULTS Patients with inflammatory MCD-like symptoms but without MCD had elevated vIL-6 levels, comparable with levels in patients with symptomatic KSHV-MCD, and had levels that were significantly greater than those in control patients with KS (P = .003). Elevated hIL-6, IL-10, and KSHV viral loads were also comparable to patients with symptomatic KSHV-MCD and significantly greater than those with KS. CONCLUSIONS A subset of patients with HIV and KSHV co-infection, but without MCD, can develop severe systemic inflammatory symptoms associated with elevated levels of KSHV vIL-6, IL-6, and KSHV viral loads. Excess lytic activation of KSHV, production of the lytic gene product vIL6, and associated immunologic dysregulation may underlie the pathophysiology of these symptoms. This IL-6-related inflammatory syndrome is important to consider in critically ill patients with HIV and KSHV co-infection.

Mother-to-child transmission of human herpesvirus-8 in South Africa

To investigate transmission of human herpesvirus (HHV)-8, 2546 mother-child pairs were recruited from rural clinics in South Africa and were tested for antibodies against lytic and latent HHV-8 antigens. The prevalence of antibodies in children increased with increasing maternal antibody titer (lytic, chi 21=26, and P<.001; latent, chi 21=55, and P<.001). HHV-8 DNA was detectable in 145 of 978 maternal saliva samples (mean virus load, 488,450 copies/mL; range, 1550-660,000 copies/mL) and in 12 of 43 breast-milk samples (mean virus load, 5800 copies/mL; range, 1550-12,540 copies/mL). The prevalence of HHV-8 DNA in maternal saliva was unrelated to latent anti-HHV-8 antibody status but was higher in mothers with the highest titers of lytic antibodies than in other mothers (34% vs. 8%; P<.001). The prevalence of lytic anti-HHV-8 antibodies in children was 13% (70/528) if the mother did not have HHV-8 in saliva and was 29% (8/28) if the mother had a high HHV-8 load (>50,000 copies/mL) in saliva (odds ratio, 2.6; 95% confidence interval, 1.1-6.2). The presence of HHV-8 DNA in maternal saliva was unrelated to latent antibodies in children. Saliva could be a route of transmission of HHV-8 from person to person, although other routes cannot be ruled out.