High levels of HIV-1 replication during the chronic phase of infection usually correlate with rapid progression to severe immunodeficiency. However, a minority of highly viremic individuals remains asymptomatic and maintains high CD4⁺ T cell counts. This tolerant profile is poorly understood and reminiscent of the widely studied nonprogressive disease model of SIV infection in natural hosts. Here, we identify transcriptome differences between rapid progressors (RPs) and viremic nonprogressors (VNPs) and highlight several genes relevant for the understanding of HIV-1–induced immunosuppression. RPs were characterized by a specific transcriptome profile of CD4⁺ and CD8⁺ T cells similar to that observed in pathogenic SIV-infected rhesus macaques. In contrast, VNPs exhibited lower expression of interferon-stimulated genes and shared a common gene regulation profile with nonpathogenic SIV-infected sooty mangabeys. A short list of genes associated with VNP, including CASP1, CD38, LAG3, TNFSF13B, SOCS1, and EEF1D, showed significant correlation with time to disease progression when evaluated in an independent set of CD4⁺ T cell expression data. This work characterizes 2 minimally studied clinical patterns of progression to AIDS, whose analysis may inform our understanding of HIV pathogenesis.

Cytotoxic T lymphocyte (CTL) responses targeting specific HIV proteins, in particular Gag, have been associated with relative control of viral replication in vivo. However, Gag-specific CTL can also be detected in individuals who do not control the virus and it remains thus unclear how Gag-specific CTL may mediate the beneficial effects in some individuals but not in others. Here, we used a 10mer peptide set spanning HIV Gag-p24 to determine immunogen-specific T-cell responses and to assess functional properties including functional avidity and cross-reactivity in 25 HIV-1 controllers and 25 non-controllers without protective HLA class I alleles. Our data challenge the common belief that Gag-specific T cell responses dominate the virus-specific immunity exclusively in HIV-1 controllers as both groups mounted responses of comparable breadths and magnitudes against the p24 sequence. However, responses in controllers reacted to lower antigen concentrations and recognized more epitope variants than responses in non-controllers. These cross-sectional data, largely independent of particular HLA genetics and generated using direct ex-vivo samples thus identify T cell responses of high functional avidity and with broad variant reactivity as potential functional immune correlates of relative HIV control.

Objectives We investigated the associations with HLA and microtubule-associated protein tau (MAPT) H1 haplotype in anti-IgLON5 disease, a recently identified disorder characterized by gait instability, brainstem dysfunction, and a prominent sleep disorder in association with IgLON5 antibodies and pathologic findings of a novel neuronal-specific tauopathy. Methods We compared the HLA alleles and MAPT H1/H1 genotype of 35 patients with anti-IgLON5 with healthy controls. The on-line server tool NetMHCIIpan 3.1 was used to predict the IgLON5 peptide binding to HLA Class II molecules. Results The HLA-DRB1*10:01-DQB1*05:01 haplotype was overrepresented in patients with anti-IgLON5 disease (OR = 54.5; 95% CI: 22.2–133.9, p < 0.0001). In addition, HLA-DQA was genotyped in 27 patients, and 25 (92.6%) of them had DQ molecules composed by DQA1*01 and DQB1*05 chains compared with 148/542 (27.3%) controls (OR = 43.9; 95% CI: 10.4–185.5, p < 0.0001). Patients DRB1*10:01 positive developed more frequently sleep or bulbar symptoms than those carrying other HLA alleles (70.0% vs 26.7%; p = 0.011). Prediction algorithms identified 2 IgLON5 peptides (1 located in the signal sequence) that showed strong binding to HLA-DRB1*10:01 and other HLA-DRB1, but not to HLA-DQA and HLA-DQB molecules. The MAPT H1/H1 homozygous genotype was present in 20/24 (83.3%) anti-IgLON5 Caucasian patients compared with 54/116 (46.5%) healthy controls (p = 0.0007). Conclusions The robust association of anti-IgLON5 disease with distinct HLA Class II molecules supports a primary autoimmune origin. The significant association of MAPT H1 haplotype also suggests that an underlying neurodegenerative process could be involved in anti-IgLON5 disease.

Plasma stromal cell–derived factor (SDF)-1 levels, SDF1-3′A polymorphism, and CXCR4+ T lymphocytes in relation to resistance to human immunodeficienc

A new autoantibody against a 155-kDa protein has been described in patients with myositis. We conducted a study to determine the occurrence and types of cancer occurring in a cohort of patients with polymyositis (PM) or dermatomyositis (DM) and analyzed the value of this autoantibody as a serologic marker of cancer-associated myositis (CAM). Serum samples from all patients were examined by protein immunoprecipitation assays with HeLa cells to determine the presence of a 155-kDa protein band. HLA-DRB1 and DQA1 typing was performed by polymerase chain reaction-reverse sequence specific oligonucleotide. Statistical analyses were carried out with the Mann Whitney U and Fisher exact tests. Associations were determined using odds ratios (ORs) with 95% confidence intervals (CI). Eighty-five patients with myositis (20 PM and 65 DM) were included. CAM was detected in 16 patients (19%), 14 with DM. The shawl sign rash was significantly more frequent in patients with CAM than in those without (p < 0.01). Adenocarcinoma was the most frequent type of cancer (87.5%). Anti-p155 autoantibody was found in 1 of the 20 (5%) patients with PM and in 15 of the 65 (23%) patients with DM. A relationship between anti-p155 and CAM was found in DM patients (OR, 23; 95% CI, 5.23-101.2). The HLA-DQA1*0102 allele was not found in any of the anti-p155-positive patients. The prevalence of CAM in our cohort was 19%. Autoantibody against p155 was highly related to CAM and could be a reliable marker of cancer in patients with DM. Abbreviations CAM = cancer-associated myositis, CI = confidence interval, DM = dermatomyositis, OR = odds ratio, PM = polymyositis.

Evidence is presented showing that a protein tyrosine phosphatase different from CD45 is present on the membrane of human hematopoietic cells. The molecule recognized by the monoclonal antibody 143-41, which has been classified as CD148 in the VI International Workshop on Leukocyte Differentiation Antigens, was immunopurified and sequenced. The sequence obtained from N-terminus as well as from two different CNBr-digested peptides showed a close identity with a previously described tyrosine phosphatase named HPTP-η/DEP-1. CD148 is present on all hematopoietic lineages, being expressed with higher intensity on granulocytes than on monocytes and lymphocytes. Interestingly, whereas it is clearly present on peripheral blood lymphocytes, it is poorly expressed on different lymphoid cell lines of T and B origin. When this protein tyrosine phosphatase was cocrosslinked with CD3, an inhibition of the normally observed calcium mobilization was observed. This inhibition correlates with a decrease in phospholipase C-γ (PLC-γ) phosphorylation and is similar to the one observed with CD45. In addition, it is shown that the crosslinking of the CD148 alone is also able to induce an increase in [Ca²⁺]_i. This increase is abolished in the presence of genistein and by cocrosslinking with CD45. These data, together with the induction of tyrosine phosphorylation on several substrates, including PLC-γ, after CD148 crosslinking, suggest the involvement of a tyrosine kinase-based signaling pathway in this process. In conclusion, the data presented show that CD148 corresponds to a previously described protein tyrosine phosphatase HPTP-η/DEP-1 and that this molecule is involved in signal transduction in lymphocytes.