Exome Sequencing Reveals a Putative Role for HLA-C*03:02 in Control of HIV-1 in African Pediatric Populations
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Date
2021
Journal Title
Journal ISSN
Volume Title
Publisher
Frontiers in Genetics
Abstract
Human leucocyte antigen (HLA) class I molecules present endogenously processed
antigens to T-cells and have been linked to differences in HIV-1 disease progression.
HLA allelotypes show considerable geographical and inter-individual variation, as does
the rate of progression of HIV-1 disease, with long-term non-progression (LTNP) of
disease having most evidence of an underlying genetic contribution. However, most
genetic analyses of LTNP have occurred in adults of European ancestry, limiting the
potential transferability of observed associations to diverse populations who carry the
burden of disease. This is particularly true of HIV-1 infected children. Here, using
exome sequencing (ES) to infer HLA allelotypes, we determine associations with HIV-
1 LTNP in two diverse African pediatric populations. We performed a case-control
association study of 394 LTNPs and 420 rapid progressors retrospectively identified
from electronic medical records of pediatric HIV-1 populations in Uganda and Botswana.
We utilized high-depth ES to perform high-resolution HLA allelotyping and assessed
evidence of association between HLA class I alleles and LTNP. Sixteen HLA alleles and
haplotypes had significantly different frequencies between Uganda and Botswana, with
allelic differences being more prominent in HLA-A compared to HLA-B and C allelotypes.
Three HLA allelotypes showed association with LTNP, including a novel association
in HLA-C (HLA-B 57:03, aOR 3.21, Pc = 0.0259; B 58:01, aOR 1.89, Pc = 0.033;
C 03:02, aOR 4.74, Pc = 0.033). Together, these alleles convey an estimated population
attributable risk (PAR) of non-progression of 16.5%. We also observed novel haplotype associations with HLA-B 57:03-C 07:01 (aOR 5.40, Pc = 0.025) and HLA-B 58:01-
C 03:02 (aOR 4.88, Pc = 0.011) with a PAR of 9.8%, as well as a previously unreported
independent additive effect and heterozygote advantage of HLA-C 03:02 with B 58:01
(aOR 4.15, Pc = 0.005) that appears to limit disease progression, despite weak LD
(r2 = 0.18) between these alleles. These associations remained irrespective of gender or
country. In one of the largest studies of HIV in Africa, we find evidence of a protective
effect of canonical HLA-B alleles and a novel HLA-C association that appears to
augment existing HIV-1 control alleles in pediatric populations. Our findings outline
the value of using multi-ethnic populations in genetic studies and offer a novel HIV-1
association of relevance to ongoing vaccine studies.
Description
Keywords
AIDS, childhood HIV, Long-term non-progression, Genetics, Genomics
Citation
Kyobe S, Mwesigwa S, Kisitu GP, Farirai J, Katagirya E, Mirembe AN, Ketumile L, Wayengera M, Katabazi FA, Kigozi E, Wampande EM, Retshabile G, Mlotshwa BC, Williams L, Morapedi K, Kasvosve I, Kyosiimire-Lugemwa J, Nsangi B, Tsimako-Johnstone M, Brown CW, Joloba M, Anabwani G, Bhekumusa L, Mpoloka SW, Mardon G, Matshaba M, Kekitiinwa A and Hanchard NA (2021) Exome Sequencing Reveals a Putative Role for HLA-C*03:02 in Control of HIV-1 in African Pediatric Populations. Front. Genet. 12:720213. doi: 10.3389/fgene.2021.720213