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 better control of HIV-1 infection through both a higher efficiency of antigen presentation to cytotoxic T lymphocytes and the triggering of activating killer immunoglobulin-like receptors on NK cells, whereas lower levels may provide poor HIV-1 control and rapid progression to AIDS. We characterized the relative amounts of HLA-C heterotrimers (heavy chain/ß2 microglobulin [ß2m]/peptide) and HLA-C free heavy chains on peripheral blood mononuclear cells (PBMCs) from healthy blood donors harboring both alleles with stable or unstable binding to ß2m/peptide. We analyzed the stability of HLA-C heterotrimers of different allotypes and the infectivity of HIV-1 virions produced by PBMCs with various allotypes. We observed significant differences in HLA-C heterotrimer stability and in expression levels. We found that R5 HIV-1 virions produced by PBMCs harboring unstable HLA-C alleles were more infectious than those produced by PBMCs 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-expression HLA-C alleles and unstable binding to ß2m/peptide might have worse control of HIV-1 infection and an intrinsically higher capacity to support viral replication.IMPORTANCE Following HIV-1 infection, some people advance rapidly to AIDS while others have 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 the modulation of 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 ß2 microglobulin/peptide; the other conformation is not bound to ß2 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 stronger immunity to HIV-1, reduced viral infectivity and effective control of HIV-1 infection, while subjects with HLA-C variants that easily dissociate from ß2 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 in the design of novel vaccine strategies and therapeutic approaches to HIV-1.

Use of DPB1 T-cell epitope algorithm among italian transplant centers: A survey on behalf of Associazione Italiana di Immunogenetica e Biologia dei Trapianti.

The HLA-DPB1 locus has been demonstrated to have a significant role on patients' outcome after allogeneic HSCT, and the so-called T-cell epitope (TCE) algorithm has been incorporated in international guidelines for the selection of unrelated donors. The purpose of the present study is to measure, through a national survey conducted on behalf of the Associazione Italiana di Immunogenetica e Biologia dei Trapianti (AIBT), the extent of awareness and use of HLA-DPB1 TCE-based algorithms during the donor search. 89% of the HLA laboratories answered to a short questionnaire and the results showed a progressive increase of the laboratories typing DPB1 in patients and their potential donors during the search (from 44% to 79% during the 2010-2019 period) as well as the application of a TCE-based algorithm for the donor choice whenever possible (from 24% to 65% during the same period). The DP-permissiveness status is detailed in the official HLA typing report by 12%, 32% and 50% of laboratories in 2010, 2015 and 2019, respectively. The present data indicate an encouraging raise in the awareness of the HLA-DPB1 role in unrelated donor selection; noteworthy, mentioning the TCE-based permissiveness status in the HLA typing report of each potential unrelated donor represents a notable mean to raise awareness among transplant physicians and to support them in their task of choosing the best donor. Nonetheless, despite the compelling evidence of the predictive ability of TCE-based algorithms, further efforts are still needed to extend its application to all transplant centers in Italy.

HIV-1-Associated Neurocognitive Disorders: Is HLA-C Binding Stability to ß2-Microglobulin a Missing Piece of the Pathogenetic Puzzle?

AIDS dementia complex (ADC) and HIV-associated neurocognitive disorders (HAND) are complications of HIV-1 infection. Viral infections are risk factors for the development of neurodegenerative disorders. Aging is associated with low-grade inflammation in the brain, i.e., the inflammaging. The molecular mechanisms linking immunosenescence, inflammaging and the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease, are largely unknown. ADC and HAND share some pathological features with AD and may offer some hints on the relationship between viral infections, neuroinflammation, and neurodegeneration. ß2-microglobulin (ß2m) is an important pro-aging factor that interferes with neurogenesis and worsens cognitive functions. Several studies published in the 80-90s reported high levels of ß2m in the cerebrospinal fluid of patients with ADC. High levels of ß2m have also been detected in AD. Inflammatory diseases in elderly people are associated with polymorphisms of the MHC-I locus encoding HLA molecules that, by associating with ß2m, contribute to cellular immunity. We recently reported that HLA-C, no longer associated with ß2m, is incorporated into HIV-1 virions, determining an increase in viral infectivity. We also documented the presence of HLA-C variants more or less stably linked to ß2m. These observations led us to hypothesize that some variants of HLA-C, in the presence of viral infections, could determine a greater release and accumulation of ß2m, which in turn, may be involved in triggering and/or sustaining neuroinflammation. ADC is the most severe form of HAND. To explore the role of HLA-C in ADC pathogenesis, we analyzed the frequency of HLA-C variants with unstable binding to ß2m in a group of patients with ADC. We found a higher frequency of unstable HLA-C alleles in ADC patients, and none of them was harboring stable HLA-C alleles in homozygosis. Our data suggest that the role of HLA-C variants in ADC/HAND pathogenesis deserves further studies. If confirmed in a larger number of samples, this finding may have practical implication for a personalized medicine approach and for developing new therapies to prevent HAND. The exploration of HLA-C variants as risk factors for AD and other neurodegenerative disorders may be a promising field of study.

Analysis of B- and T-cell clonality and HLA class II alleles in patients with idiopathic thrombocytopenic purpura: correlation with Helicobacter pylori infection and response to eradication treatment.

Many authors have recently found a positive correlation between Helicobacter pylori infection and idiopathic thrombocytopenic purpura (ITP), the most common autoimmune hematological disorder. In order to clarify the pathogenic mechanism of H. pylori-associated ITP, we have investigated 52 consecutive ITP adult patients for Helicobacter pylori infection, B- and T-cell clonality and HLA class II alleles. Thirty-four ITP patients (65.4%) were infected by H. pylori and bacterium eradication was accompanied by a long-term platelet response in 17 (53.1%) of them. A B-cell clonality was found in three patients (5.8%, two patients H. pylori-negative and one patient H. pylori-positive). The ITP patients with H. pylori infection showed a HLA-DRB1*11, *14 and -DQB1*03 frequencies significantly higher and a -DRB1*03 frequency significantly lower than in H. pylori-negative patients. Moreover, an HLA-DQB1*03 pattern was associated with a higher probability of platelet response to eradication treatment. If our study documents the efficacy of eradication treatment in H. pylori-infected ITP patients, it may also help to identify different subgroups of ITP patients with probably different pathogeneses of thrombocytopenia and, finally, different responses to eradication treatment.