Abstract
HLA-C has been demonstrated to associate with HIV-1 envelope glycoprotein (Env). Virions lacking HLA-C have reduced infectivity and increased susceptibility to neutralizing antibodies. Like all others MHC-I molecules, HLA-C requires β2-microglobulin (β2m) for appropriate folding and expression on the cell membrane but this association is weaker, thus generating HLA-C free-chains on the cell surface. In this study, we deepen the understanding of HLA-C and Env association by showing that HIV-1 specifically increases the amount of HLA-C free chains, not bound to β2m, on the membrane of infected cells. The association between Env and HLA-C takes place at the cell membrane requiring β2m to occur. We report that the enhanced infectivity conferred to HIV-1 by HLA-C specifically involves HLA-C free chain molecules that have been correctly assembled with β2m. HIV-1 Env-pseudotyped viruses produced in the absence of β2m are less infectious than those produced in the presence of β2m. We hypothesize that the conformation and surface expression of HLA-C molecules could be a discriminant for the association with Env. Binding stability to β2m may confer to HLA-C the ability to preferentially act either as a conventional immune-competent molecule or as an accessory molecule involved in HIV-1 infectivity.
Highlights
HLA-C have reduced infectivity and increased susceptibility to neutralizing antibodies
The results showed that the expression of HLA-C free chains (L31 antibody) at the cell surface correlated with the expression of HIV-1 Env (2G12 antibody), both decreasing at later time points
This observation was further confirmed in another cell line (PM1), where the TNF-α-induced increase of HIV-1 replication correlated with the upregulation of HLA-C free chains at the cell membrane
Summary
HLA-C have reduced infectivity and increased susceptibility to neutralizing antibodies. HLA-C surface expression appears lower for those alleles which bind miRNA148a, and higher for those alleles escaping this specific post-transcriptional regulation[7] Consistent with these findings, low expression alleles such as C * 04 and C * 07 have been associated with a more rapid progression toward AIDS than high expression alleles, such as C * 02, C * 06, and C * 128. In a recent work it has been demonstrated that, in most primary HIV-1 clones, Vpu is able to down-regulate HLA-C but not HLA-A and HLA-B, escaping the HLA-C restricted CTLs response, possibly depending on the prevailing host immune pressure: natural killer (NK) versus CTL10 Adding complexity to this matter, a recent study failed to confirm the association between HLA-C cell surface expression and the −35 Kb SNP; rather, a high-allelic variability in HLA-C mRNA expression has been demonstrated, suggesting that the control of HLA-C expression might be more complex than expected[11]. HLA-C is involved in HIV-1 infection through different and apparently opposite mechanisms: a) the increase of CTLs recognition leading to the lysis of HIV-1 infected cells, b) the inhibition of NK cell recognition, leading to the enhancement of virion infectivity and c) the association with the HIV-1 envelope protein[14]
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