Diverse genotypes of Kaposi's sarcoma associated herpesvirus (KSHV) identified in infant blood infections in African childhood-KS and HIV/AIDS endemic region

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) has been associated with several neoplasias, including childhood endemic Kaposi's sarcoma (KS). It is possible that strain genotypes could contribute to the differences in regional presentation (mainly sub-Saharan Africa), childhood infection, lack of male sex bias, distinct disseminated forms and rapid fatality observed for childhood endemic KS. Early studies, at the advent of the HIV/AIDS epidemic, identified only the K1-A5 genotype in childhood KS biopsies as well as blood of a few HIV positive and negative febrile infants in Zambia, a highly endemic region. This current enlarged study analyses blood infections of 200 hospitalized infants (6-34 months age) with symptoms of fever as well as upper respiratory tract infection, diarrhoea, rash or rhinitis. KSHV and HIV viraemia and were prevalent in this group, 22% and 39%, respectively. Multiple markers at both variable ends of the genome (K1, K12, and K14.1/K15) were examined, showing diverse previously adult-linked genotypes (K1 A2, A5, B, C3, D, with K12 B1 and B2 plus K14.1/K15 P or M) detected in both HIV positive and negative infants, demonstrating little restriction on KSHV genotypes for infant/childhood transmission in a childhood endemic KS endemic region. This supports the interpretation that the acquisition of childhood KSHV infections and subsequent development of KS are due to additional co-factors.

Fig. 1

Sequence analyses of K1 variable region, VRI loop, identifies genotype diversity in childhood KSHV from African endemic region. The K1 region was PCR amplified from blood DNA, sequenced and aligned against published representatives of K1 genotypes [Zong et al., 1999]. Dashes indicated identity.

Fig. 2

Phylogenetic tree of K1 sequences from childhood KSHV blood infections in comparison to reference genotypes from Figure 1 shows extensive diversity. Scale and branch lengths indicate relative genetic distance. In the bootstrap analyses the multiple alignment was resampled generating 100 trees. Bootstrap values achieved are expressed in percentages and placed at the nodes.

Fig. 3

Nucleotide changes in the K12 region shows B genotypes identified in African regions. Reference genotypes are shown (A, AC, M, B1, and B2), including Ugandan reference sequences from adultKS biopsy materials, compared to the Zambian infant patients blood genotypes showing B1 and B2. The K12 segment is in the reverse complement orientation (coding) from the genomic sequence. The positions of nucleotide variation and reference sequences are as shown previously with position 1 as in [Poole et al., 1999; Kakoola et al., 2001] or 118,065 in the BC1 genomic sequence, or position 51 in Poole et al. [1999], (positions −22 is 30, and 64 is 115 in Poole et al. [1999];). K12ORF, Kaposin A, ends at position 147 as inPoole et al. [1999] and Kakoola et al. [2001] or 117,919 in the BC1 genome [Russo et al., 1996]. The PCR product was from 118,116–117, 469. Hyphens and dots indicate identical or deleted residues.

Fig. 4

Coding changes in the K12 Kaposin A gene. Zambian infant blood KSHV K12 B genotypes (from Fig. 3) compared to protein encoded by reference P type genome (GK18) [Rezaee et al., 2006]. A disrupted motif reported required for transformation is underlined [Tomkowicz et al., 2005].