The Role of the HLA B and C Loci in Human Herpesvirus 8 Replication in a Ugandan Population

Abstract

Kaposi sarcoma (KS) is one of the most common cancers among individuals with HIV, and the most common form of cancer in regions of Africa. Human herpesvirus 8 (HHV-8) is the etiologic factor in the development of KS; infection with HHV-8 is necessary, but not sufficient for the progression from primary HHV-8 infection to the development of KS. Since not all HIV-positive individuals infected with HHV-8 develop KS, it has been hypothesized that human genetic variation may play a role in the risk of HIV-associated KS. Human leukocyte antigen (HLA) loci mediate immune responses to viral infection, and genetic variants at HLA loci have been associated with control of oncoviruses in prior studies. We conducted a pilot study to describe the distribution of HLA-B and HLA-C loci in a Ugandan population of families with one family member diagnosed with HIV-related KS. The goals of this study included: (i) a description of the distribution of HLA-B and HLA-C alleles in the overall cohort; (ii) a description of the distribution of HLA-B and HLA-C alleles when the cohort was stratified by KS status and level of HHV-8 viral replication; and (iii) an assessment of potential associations between HHV-8 replication and HLA-B and HLA-C loci using a global transmission disequilibrium test. The sample consisted of 82 individuals in 22 families. HLA-B and HLA-C loci were highly diverse in this population, with higher heterozygosity at both loci compared with the average loci heterozygosity across populations. HLA-B allele frequencies ranged from 0.01 to 0.10, and HLA-C allele frequencies ranged from .01 to .19. HLA-C*06:02:01G and HLA-C*04:01:01G were overrepresented in both KS-positive and viral replication allele pools, indicating a potential future area of study. No significant association between any HLA-B or HLA-C allele and HHV-8 replication was found by a global transmission disequilibrium test. This study generates hypotheses for further investigation and establishes a knowledge base for future studies.