Abstract
Several studies demonstrated a relevant role of polymorphisms located within the HLA-B and -C loci and the Killer Immunoglobulin Receptors (KIRs) 3DL1 and 3DS1 in controlling HIV-1 replication. KIRs are regulatory receptors expressed at the surface of NK and CD8+ T-cells that specifically bind HLA-A and -B alleles belonging to the Bw4 supratype and all the -C alleles expressing the C1 or C2 supratype. We here disclose a novel signature associated with the Elite Controller but not with the long-term nonprogressor status concerning 2DS activating KIRs and HLA-C2 alleles insensitive to miRNA148a regulation. Overall, our findings support a crucial role of NK cells in the control of HIV-1 viremia.
Highlights
Several studies demonstrated a relevant role of polymorphisms located within the HLA-B and -C loci and the Killer Immunoglobulin Receptors (KIRs) 3DL1 and 3DS1 in controlling HIV-1 replication
The presence of activating KIR genes, namely 3DS1, 2DS1 and 2DS5 on chromosome 19 (Fig. 1A) clearly distinguished the 40 Elite Controllers (EC) from the 111 healthy blood donors (HD) and to some extent from the[189] HIV P, whereas the 39 Long Term Non Progressors (LTNP) segregated in an intermediate position between EC and P
Both EC and LTNP segregated independently from P and HD for chromosome 6-associated markers (Fig. 1B), that included homozygosity of Single Nucleotide Polymorphism (SNP) rs9264942C, commonly termed −3 5C, and of SNP rs67384697del (263del) as well as the presence of HLA-B alleles both belonging to the Bw4-I80 supratype
Summary
Several studies demonstrated a relevant role of polymorphisms located within the HLA-B and -C loci and the Killer Immunoglobulin Receptors (KIRs) 3DL1 and 3DS1 in controlling HIV-1 replication. Among the best characterized correlates of these rare (1–2% of infected individuals) conditions of natural control of HIV-1 disease progression, there are genetic factors, mostly associated to the HLA Class I loci, in addition to the heterozygous 32-bp deletion of CCR5 typical of a significant fraction of LTNP3. These findings have been largely interpreted and correlated with a robust CD8+ cytotoxic T cell (CTL) response keeping in check the number of infected cells[4]. This SNP was shown to partially influence cell surface expression of HLA-C with weakly expressed alleles possessing an intact miR148a binding site (263 G) and highly expressed alleles having a deletion in the site (263del), escaping the regulation by that microRNA24
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