Stability and expression levels of HLA-C on the cell membrane modulate HIV-1 infectivity

HLA-C expression is associated with a differential ability to control HIV-1 infection. Higher HLA-C levels may lead to a better control of HIV-1 infection through both a higher efficiency of antigen presentation to cytotoxic T lymphocytes (CTLs), as well as the triggering of activating Killer Immunoglobulin like receptors (KIR) on NK-cells, whereas lower levels may provide a poor HIV-1 control and a rapid progression toward AIDS.We characterized the relative amount of HLA-C heterotrimers (heavy chain/\u3b22m/peptide) and HLA-C free heavy chains on PBMC from healthy blood donors harboring both alleles with stable or unstable binding to \u3b22m/peptide. We analyzed the stability of HLA-C heterotrimers of different allotypes and the infectivity of HIV-1 virions produced by PBMC with various allotypes.We observed significant differences in HLA-C heterotrimers stability and in expression levels. We found that R5 HIV-1 virions produced by PBMC harboring unstable HLA-C alleles were more infectious than those produced by PBMC carrying the stable variants.We propose that HIV-1 infectivity might depend both on the amounts of HLA-C molecules and on their stability as trimeric complex. According to this model, individuals with low expressed HLA-C alleles and unstable binding to \u3b22m/peptide might have a worse control of HIV-1 infection and an intrinsically higher capacity to support viral replication.IMPORTANCE Following HIV-1 infection, some people advance rapidly toward AIDS while others have a slow disease progression. HLA-C, a molecule involved in immunity, is a key determinant of HIV-1 control.Here we reveal how HLA-C variants contribute to modulate viral infectivity. HLA-C is present on the cell surface in two different conformations: the immunologically active conformation is part of a complex that includes \u3b22-microglobulin/peptide; the other conformation is not bound to \u3b22-microglobulin/peptide and can associate with HIV-1, increasing its infectivity. Individuals with HLA-C variants with a predominance of immunologically active conformations would display a stronger immunity against HIV-1, a reduced viral infectivity and an effective control of HIV-1 infection, while subjects with HLA-C variants that easily dissociate from \u3b22-microglobulin/peptide would have a reduced immunological response to HIV-1 and produce more infectious virions.This study provides new information that could be useful to design novel vaccine strategies and therapeutic approaches against HIV-1

A fast and reliable method for detecting SNP rs67384697 (Hsa-miR-148a binding site) by a single run of allele-specific real-time PCR

Surface expression of HLA-class I molecules is critical for modulating T/NK lymphocytes' effector functions. Amongst HLA molecules, HLA-C, the most recently evolved form of class I antigens, is subjected to both transcriptional and multiple post transcriptional regulation mechanisms affecting its cell surface expression. Amongst the latter a region placed in the 3' untranslated region (UTR) of HLA-C transcript contains the single nucleotide polymorphism (SNP) rs67384697 "G-ins/del" that has been found to be strictly associated with surface levels of HLA-C allomorphs due to the effect on the binding site of a microRNA (Hsa-miR-148a). Higher expression of HLA-C has proved to influence HIV-1 infection via a better control of viremia and a slower disease progression. More importantly, the analysis of SNP rs67384697 "G-ins/del" combined with the evaluation of the HLA-Bw4/-Bw6 C1/C2 supratype, as well as the KIR genetic asset, has proved to be pivotal in defining the status of Elite Controllers in the caucasian population. Here we describe a new reliable and fast method of allele-specific real-time PCR to monitor the integrity/disruption of the binding site of the microRNA Hsa-miR-148a in a high-throughput format that can be easily applied to studies involving large cohorts of individuals. This article is protected by copyright. All rights reserved

Correction for Parolini et al., "Stability and Expression Levels of HLA-C on the Cell Membrane Modulate HIV-1 Infectivity"

Erratum for Stability and Expression Levels of HLA-C on the Cell Membrane Modulate HIV-1 Infectivity. [J Virol. 2018

Activating Killer Immunoglobulin Receptors and HLA-C: A successful combination providing HIV-1 control

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

Measurement of CP violation observables and parameters for the decays B-+/--> DK*+/-

We study the decay B--> DK*- using a sample of 379x10(6) Upsilon(4S)-> BB events collected with the BABAR detector at the PEP-II B factory. We perform a Gronau-London-Wyler analysis where the D meson decays into either a CP-even (CP+) eigenstate (K+K-, pi(+)pi(-)), CP-odd (CP-) eigenstate (K-S(0)pi(0), K-S(0)phi, K-S(0)omega) or a non-CP state (K-pi(+)). We also analyze D meson decays into K+pi(-) from a Cabibbo-favored D-0 decay or doubly suppressed D-0 decay [Atwood-Dunietz-Soni (ADS) analysis]. We measure observables that are sensitive to the Cabibbo-Kobayashi-Maskawa angle gamma: the partial-rate charge asymmetries A(CP +/-), the ratios R-CP +/- of the B-decay branching fractions in CP +/- and non-CP decay, the ratio R-ADS of the charge-averaged branching fractions, and the charge asymmetry A(ADS) of the ADS decays: A(CP+)=0.09 +/- 0.13 +/- 0.06, A(CP-)=-0.23 +/- 0.21 +/- 0.07, RCP+=2.17 +/- 0.35 +/- 0.09, RCP-=1.03 +/- 0.27 +/- 0.13, R-ADS=0.066 +/- 0.031 +/- 0.010, and A(ADS)=-0.34 +/- 0.43 +/- 0.16, where the first uncertainty is statistical and the second is systematic. Combining all the measurements and using a frequentist approach yields the magnitude of the ratio between the Cabibbo-suppressed and favored amplitudes, r(B)=0.31 with a one (two) sigma confidence level interval of [0.24, 0.38] ([0.17, 0.43]). The value r(B)=0 is excluded at the 3.3 sigma level. A similar analysis excludes values of gamma in the intervals [0, 7]degrees, [55, 111]degrees, and [175, 180]degrees ([85, 99]degrees) at the one (two) sigma confidence level

Correlated leading baryon-antibaryon production in e(+)e(-) -> c(c)over-bar -> Lambda(+)(c)(Lambda)over-bar(c)(-)X

We present a study of 649 +/- 35 e(+)e(-) -> c (c) over bar events produced at root s approximate to 10.6 GeV containing both Lambda(+)(c) baryon and a (Lambda) over bar (-)(c) antibaryon. The number observed is roughly 4 times that expected if the leading charmed hadron types are uncorrelated, confirming an observation by the CLEO Collaboration. We find a 2-jet topology in these events but very few additional baryons, demonstrating that the primary c and (c) over bar are predominantly contained in a correlated baryon-antibaryon system. In addition to the charmed baryons we observe on average 2.6 +/- 0.2 charged intermediate mesons, predominantly pions, carrying 65% of the remaining energy