Jackson Orem

A Molecular Link between Malaria and Epstein–Barr Virus Reactivation

Although malaria and Epstein–Barr (EBV) infection are recognized cofactors in the genesis of endemic Burkitt lymphoma (BL), their relative contribution is not understood. BL, the most common paediatric cancer in equatorial Africa, is a high-grade B cell lymphoma characterized by c-myc translocation. EBV is a ubiquitous B lymphotropic virus that persists in a latent state after primary infection, and in Africa, most children have sero-converted by 3 y of age. Malaria infection profoundly affects the B cell compartment, inducing polyclonal activation and hyper-gammaglobulinemia. We recently identified the cystein-rich inter-domain region 1α (CIDR1α) of the Plasmodium falciparum membrane protein 1 as a polyclonal B cell activator that preferentially activates the memory compartment, where EBV is known to persist. Here, we have addressed the mechanisms of interaction between CIDR1α and EBV in the context of B cells. We show that CIDR1α binds to the EBV-positive B cell line Akata and increases the number of cells switching to the viral lytic cycle as measured by green fluorescent protein (GFP) expression driven by a lytic promoter. The virus production in CIDR1α-exposed cultures was directly proportional to the number of GFP-positive Akata cells (lytic EBV) and to the increased expression of the EBV lytic promoter BZLF1. Furthermore, CIDR1α stimulated the production of EBV in peripheral blood mononuclear cells derived from healthy donors and children with BL. Our results suggest that P. falciparum antigens such as CIDR1α can directly induce EBV reactivation during malaria infection that may increase the risk of BL development for children living in malaria-endemic areas. To our knowledge, this is the first report to show that a microbial protein can drive a latently infected B cell into EBV replication.

AIDS-associated cancer in developing nations

Purpose of review With the emergence of the highly active antiretroviral therapy era, it is apparent that the incidence of Kaposi sarcoma, in particular, and lymphoma in patients with AIDS is declining, especially in regions of the world where these regimens are routinely available. The burden of HIV infection and AIDS is greatest in the developing world, and no doubt neoplastic complications are increasingly encountered. The purpose of this review is to highlight recent developments of this aspect of the AIDS epidemic in the developing world. Recent findings It was readily apparent that the incidence of Kaposi sarcoma sharply increased after the onset of the AIDS epidemic in developing countries. By the end of the second decade of the epidemic, non-Hodgkin lymphoma is increasing in incidence and the natural history of Burkitt lymphoma is evolving in the backdrop of HIV infection as well. Cervical cancer is the most common cancer in women in many developing countries, yet the true impact of HIV infection on the development of this neoplasm is not fully understood. Squamous cell carcinoma of the conjunctiva appears to be a unique AIDS-associated neoplasm that is encountered in sub-Saharan Africa as well. Finally, although the epidemiologic and clinicopathologic features for many AIDS-associated neoplasms are well characterized in developing regions of the world, there is a paucity of data on the therapeutic approach to these tumors in this setting. Summary It is apparent that as the AIDS pandemic proceeds, the burden of neoplastic diseases is increasing in developing nations. Current therapeutic approaches are not well documented. Pragmatic prevention and therapeutic interventions suitable for the resource-constrained setting are clearly needed.

Clinical presentation and outcome of epidemic Kaposi sarcoma in Ugandan children.

Kaposi sarcoma (KS) is one of the most common pediatric cancers in sub‐Saharan Africa. Few data are available about the clinical presentation or response to treatment of children with epidemic (HIV‐associated) KS.

Endemic Burkitt's lymphoma as a polymicrobial disease New insights on the interaction between Plasmodium falciparum and Epstein―Barr virus

Despite the well-established relationship between endemic Plasmodium falciparum malaria and Epstein-Barr virus (EBV) infection in the genesis of endemic Burkitts lymphoma (eBL), very little research has examined the interaction between these two pathogens. eBL, the most prevalent childhood cancer in equatorial Africa where malaria is holoendemic, is a high-grade B cell lymphoma characterized by a c-myc translocation and the consistent presence of EBV. After primary infection, EBV establishes a life-long persistent infection characterized by virus shedding into saliva. African children are infected early in life and most have sero-converted by 3 years of age while sero-conversion tends to occur later in developed countries. Acute and chronic malaria infections profoundly affect the B cell compartment, inducing polyclonal activation, hyper-gammaglobulinemia and a dramatic increase in the levels of circulating EBV. In this review we present and discuss recent data suggesting a molecular link between the parasite, the B cell and EBV and provide evidence that adds to the concept of polymicrobial disease pathogenesis in eBL. Following the observation of EBV reactivation in children living in malaria endemic areas and its relationship with acute malaria infection, we identified the cystein-rich inter-domain region 1 alpha (CIDR1 alpha) of the Plasmodium falciparum membrane protein 1 as a polyclonal B cell activator. CIDR1 alpha increases B cell survival and preferentially activates the memory compartment where EBV is known to persist. Analysis of the mechanisms of interaction between CIDR1 alpha and EBV in the context of B cells demonstrated that CIDR1 alpha induces virus production in the EBV-infected B cell line Akata and in latently infected primary B cells derived from the peripheral blood of healthy carriers and children with eBL. This is the first demonstration that EBV can be reactivated directly by another pathogen. Our results suggest that P. falciparum antigens such as PfEMP1 can directly induce EBV reactivation during malaria infections. The increased viral load and the concomitant polyclonal B cell activation with enhanced B cell survival may augment the risk of eBL development in children living in malaria-endemic areas.

Clinical characteristics and outcome of children with Burkitt lymphoma in Uganda according to HIV infection.

Characteristics of children with Burkitt lymphoma (BL) and HIV infection have not been described in Uganda before.

Impact of HIV Infection and Kaposi Sarcoma on Human Herpesvirus-8 Mucosal Replication and Dissemination in Uganda

Introduction Kaposi sarcoma (KS) is the leading cause of cancer in Uganda and occurs in people with and without HIV. Human herpesvirus-8 (HHV-8) replication is important both in transmission of HHV-8 and progression to KS. We characterized the sites and frequency of HHV-8 detection in Ugandans with and without HIV and KS. Methods Participants were enrolled into one of four groups on the basis of HIV and KS status (HIV negative/KS negative, HIV positive/KS negative, HIV negative/KS positive, and HIV positive/KS positive). Participants collected oral swabs daily and clinicians collected oral swabs, anogenital swabs, and plasma samples weekly over 4 weeks. HHV-8 DNA at each site was quantified by polymerase chain reaction (PCR). Results 78 participants collected a total of 2063 orals swabs and 358 plasma samples. Of these, 428 (21%) oral swabs and 96 (27%) plasma samples had detectable HHV-8 DNA. HHV-8 was detected more frequently in both the oropharynx of persons with KS (24 (57%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p = 0.002) and the peripheral blood (30 (71%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p<0.001). In a multivariate model, HHV-8 viremia was more frequent among men (IRR = 3.3, 95% CI = 1.7–6.2, p<0.001), persons with KS (IRR = 3.9, 95% CI = 1.7–9.0, p = 0.001) and persons with HIV infection (IRR = 1.7, 95% CI = 1.0–2.7, p = 0.03). Importantly, oral HHV-8 detection predicted the subsequent HHV-8 viremia. HHV-8 viremia was significantly more common when HHV-8 DNA was detected from the oropharynx during the week prior than when oral HHV-8 was not detected (RR = 3.3, 95% CI = 1.8–5.9 p<0.001). Genital HHV-8 detection was rare (9 (3%) of 272 swabs). Conclusions HHV-8 detection is frequent in the oropharynx and peripheral blood of Ugandans with endemic and epidemic KS. Replication at these sites is highly correlated, and viremia is increased in men and those with HIV. The high incidence of HHV-8 replication at multiple anatomic sites may be an important factor leading to and sustaining the high prevalence of KS in Uganda.

Ocular surface squamous neoplasia in patients with HIV infection in sub-Saharan Africa.

Purpose of review Ocular surface squamous neoplasia (OSSN) in sub-Saharan countries is an aggressive tumor that affects younger patients and appears to be increasing in incidence. There are data to suggest the association of this disease with solar radiation exposure, HIV, and human papilloma virus (HPV). This trend possibly reflects the association of the high incidence of HIV, concomitant high incidence of exposure to HPV, and the solar radiation exposure that people in this region of the world receive. We undertook a PubMed search with the terms ‘ocular surface squamous neoplasia’, ‘conjunctival carcinoma’, ‘HIV’ and ‘HPV’, and ‘sub-Saharan/Africa’ to ascertain the scope of the problem and to review the available data, with an emphasis on publications of 2009 and the first quarter of 2010. Recent findings There is increasing evidence of a significant association between HIV seropositivity and OSSN. The role of HPV as contributing to the cause of OSSN is being investigated. Summary Patients with conjunctival cancer in sub-Saharan Africa are typically younger and more than 50% have underlying HIV infection. Initial presentation can be asymptomatic; however, many of these patients have advanced disease before they seek medical help and OSSN appears to have a more aggressive clinical course in sub-Saharan Africa. Treatment in Africa is primarily surgical. Chemotherapy and antiviral agents have been used. A diagnosis of OSSN in younger patients in sub-Saharan Africa should prompt HIV serotesting.

The management of children with Kaposi sarcoma in resource limited settings

Kaposi sarcoma (KS) is common where HIV infection is endemic. Antiretroviral therapy (ART) has reduced the incidence in well‐resourced settings but in some parts of the world access to ART is delayed. These recommendations are for use where only minimal requirements for treatment are available. Consensus was sought for the management of childhood HIV‐associated KS in this setting. There are no randomised controlled studies of chemotherapy for KS in children and these recommendations have drawn on consensus of a group of experts and published reports from studies in adults. Pediatr Blood Cancer 2013; 60: 538–542.

Contribution of HIV infection to mortality among cancer patients in Uganda

Objective:HIV infection is associated with cancer risk. This relationship has resulted in a growing cancer burden, especially in resource-limited countries where HIV is highly prevalent. Little is known, however, about how HIV affects cancer survival in these settings. We therefore investigated the role of HIV in cancer survival in Uganda. Design:Retrospective cohort (N = 802). Methods:Eligible cancer patients were residents of Kyadondo County, at least 18 years of age at cancer diagnosis, and diagnosed between 2003 and 2010 with one of the following: breast cancer, cervical cancer, non-Hodgkins lymphoma, Hodgkins lymphoma, or esophageal cancer. Patients were classified as HIV-infected at cancer diagnosis based on a documented positive HIV antibody test, medical history indicating HIV infection, or an HIV clinic referral letter. The primary outcome, vital status at 1 year following cancer diagnosis, was abstracted from the medical record or determined through linkage to the national hospice database. The risk of death during the year after cancer diagnosis was compared between cancer patients with and without evidence of HIV infection using Cox proportional hazards regression. Results:HIV-infected cancer patients in Uganda experienced a more than two-fold increased risk of death during the year following cancer diagnosis compared to HIV-uninfected cancer patients [hazard ratio 2.28; 95% confidence interval (CI) 1.61–3.23]. This association between HIV and 1-year cancer survival was observed for both cancers with (hazard ratio 1.56; 95% CI 1.04–2.34) and without (hazard ratio 2.68; 95% CI 1.20–5.99) an infectious cause. Conclusion:This study demonstrates the role of HIV in cancer survival for both cancers with and without an infectious cause in a resource-limited, HIV-endemic setting.

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

Introduction 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. Methods and Findings 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/mm3; IQR 11–156 cells/mm3) than men (124 cells/mm3; IQR 22–254 cells/mm3) (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. Conclusions 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.