Investigation of human leukocyte antigen alleles as risk factors for cryptococcal disease in Ugandan individuals with HIV.

Cryptococcus neoformans is an opportunistic fungal infection and a leading cause of HIV-associated meningitis, contributing significantly to AIDS-related mortality, especially in Africa. Despite advancements in treatment, case fatality rates remain high, emphasizing the need for a better understanding of host immune responses. This study investigated the association between variation in the human leukocyte antigen (HLA) genes and the risk of cryptococcal disease in Ugandan individuals with HIV. We first described the allele prevalence in a prospectively enrolled Ugandan population using next-generation sequencing at a four-field resolution for classic HLA class I and II genes. We then conducted a case-control analysis involving 137 participants categorized as: 1) disseminated cryptococcosis but without meningitis, 2) cryptococcal meningitis, and 3) controls with similar degree of HIV disease but without cryptococcal infection. Across 66 unique alleles that met criteria for analysis, we found no significant associations between HLA variation and altered risk of disseminated cryptococcosis or cryptococcal meningitis after adjusting for multiple comparisons. However, before multiple comparisons correction, HLA-DPB1*04:01 demonstrated lower odds ratios for both disseminated disease and cryptococcal meningitis. Using public online databases, we analyzed predicted Cryptococcus peptide binding to HLA-DPB1*04:01 with predicted interferon-gamma responses and identified 121 viable peptides-leading us to hypothesize a role for the leading epitopes. This research underscores the need to further investigate the importance of the HLA system for host-pathogen interactions in HIV-associated cryptococcal disease.