Selected genes of Human herpesvirus-8 associated Kaposi’s sarcoma among patients with Human Immunodeficiency Virus-1 and Acquired Immunodeficiency Disease Syndrome

Introduction Kaposi's sarcoma (KS) is a kind of cancer that causes flat or raised lesions containing Human herpes virus 8 (HHV8). The KS lesions are common among immunosuppressed HIV patients. Highly Active Antiretroviral (HHART) treats and prevents the development of KS. The objective of this study was to determine the presence of K1 and K15 (predominant alleles) genes in Kaposi's sarcoma-associated herpes virus (KSHV) among immunosuppressed patients due to HIV-1. Methods This was a cross-sectional descriptive study where consecutive sampling technique was adopted to pick archived tissue blocks from the Thematic Unit of Anatomic Pathology, Department of Human Pathology, College of Health Sciences, University of Nairobi and Department of Laboratory Medicine, Histology Section, Kenyatta National Hospital. Results Upon staining 81 tissue blocks with H & E, 84% (68/81) were diagnosed as KS and 16% (13/81) as KS-like. The K1 and K15 (P) genes were both detected at 88.9% (72/81) in the tissue blocks, with 95.8% (69/72) detection from KS and 4.2% (3/72) from the KS-like. Conclusion The K1 and K15 (P) genes of KSHV were present among the immunosuppressed patients with Human Immunodeficiency Virus (HIV)-1. It is important to carry out K1 and K15 (P) genes detection on tissues that are diagnosed as KS or KS-like by histology technique.


Introduction
Current studies indicate that all types of Kaposi's sarcoma (KS) are caused by Human Herpes Virus (HHV)-8 infections, and the difference in them is attributed by the contributions of many cofactors [1].
Genetic or environmental factors are essential for progression of KS resulting to heterogeneous circulation of the virus in different populations [2]. Immunosuppression due to Human Immunodeficiency Virus (HIV)-1 can result in the manifestation of Kaposi's sarcoma tumors [3]. The genome of HHV-8 is about 140.5 Kilo base pair, and encompasses several terminal repeats [4]. The naming of HHV-8 genes is based on the genomic location, and the letter 'K' is deduced from Kaposi's sarcoma human virus (KSHV) [5].
The HHV-8 genes have been observed to play a role in the KS pathogenesis. K1 gene stimulates and augments other cells in a paracrine manner. Manifestation of KS is heightened when K1 gene which encodes for inflammation unites with the HIV-1 Tat protein [6].
K15 gene is located at the right end of HHV-8 genome and occurs in two alleles as P (Predominant) and M (minor). It has been shown to contribute to the angiogenic properties of the KSHV [7]. Viral pathogenesis of HHV-8 associated KS has been attributed to the interactions between host immune responses, K1 and K15 genes. In addition, K1 and K15 genes have also been detected in cells during latency period and have been linked to viral neoplasia [8]. The geographical distribution of HHV-8 has been well defined. However, what remains a puzzle is the reason for its high prevalence in Africa and Middle East and a relatively lower prevalence in United States and Northern Europe [9]. Studies have suggested the possibility of HHV-8 being transmitted through oral-fecal route but this still yet to be established [10]. The precise mode of transmission of HHV-8 is still not known but, the virus has been successfully detected in semen and saliva [11]. It is not recommended to test children and adults on a routine basis, for this reason the serological status of HHV-8 in patients infected with HIV is frequently unknown [12]. results from a nationally representative study [17], q = 0.944, d^2 = 0.05^2, n = 1.962 X ((0.056) X (1-0.056))/(0.05)^2 = 81. The data was analyzed using SPSS version 21 where the relationship between K1, K15 (P) genes and clinicopathologic factors were tested by chisquare, multiple logistic analysis and t-test. A P value < 0.05 was considered statistically significant.

Results
The K1 and K15 (P) genes detected as positive were 88.9% (72/81) and negative was 11.1% (9/81). Among the 88.9% tissue bocks that were positive for the targeted HHV-8 genes, 41.7% (30/72) were from female and 58.3% (30/72) male. All the subjects whose tissue blocks were retrieved for this study were found to be HIV positive.  [21]. In Zimbabwe, the existence of K1 diversity was evaluated and it was observed that there was no significant relationship that was found to exist amongst K1 subtypes and the clinico-demographic features among the 65 AIDS-KS patients [22]. The results of this study will add to the literature on the existing list of countries that have successfully detected K1 and K15 (P) genes associated with AIDS-KS in Africa. The crude prevalence odds ratio (POR) from Table 1 indicated that none of the variables were found significant (P < 0.05); but some variables like gender, CD4 cell count, treatment and distribution of KS lesions showed a strength in the association: gender for example, we noticed that compared to females, males were twice represented among those with K1 and K5 (P) genes cases.
These findings were in agreement with another study [23] where it was observed that in Africa, tumors associated with KS were likely to be diagnosed in male patients. From the registry records where the bio-data and clinical information of the patients, whose tissue blocks were used in this study, none had a CD4 count above 350 cell/ mm 3 .
Other studies [24,25] have also indicated that CD4 cell count <350 cells/ mm 3 are linked to high risk of developing KS whether one is on HIV treatment or not. However, recommendations have been made on the need to lookout on KS cases in subjects with high CD4 cell count [24]. For treatment, HAART naive group in this study were found to be twice represented among the K1 and K5 (P) genes cases compared to those on treatment. Typically, when a patient with AIDS associated KS adheres to antiretroviral therapy (ART), their CD4 cell count is elevated and clinical presentation of KS tumors either stabilize or resolve [26]. However, when a patient is on ganciclovir (an antiviral used in the treatment of various forms of herpes) the replication of KSHV is inhibited [27], although after the manifestation of KS tumors these drugs may not be of use. Confirmed AIDS-KS patients should be on highly active antiretroviral therapy (HAART) to achieve 60-90% These findings were consistent with a study conducted in Uganda [33] where women were less likely to have nodular lesions of KS compared to men. In the Uganda study, reduced rate of KS among females might have been due to gender related factors that include hormonal, environmental or genetic factors.