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OBJECTIVE: To explore if oral insulin could delay onset of stage 3 type 1 diabetes (T1D) among patients with stage 1/2 who carry HLA DR4-DQ8 and/or have elevated levels of IA-2 autoantibodies (IA-2As). RESEARCH AND METHODS: Next-generation targeted sequencing technology was used to genotype eight HLA class II genes (DQA1 , DQB1 , DRB1 , DRB3 , DRB4 , DRB5 , DPA1 , and DPB1) in 546 participants in the TrialNet oral insulin preventative trial (TN07). Baseline levels of autoantibodies against insulin (IAA), GAD65 (GADA), and IA-2A were determined prior to treatment assignment. Available clinical and demographic covariables from TN07 were used in this post hoc analysis with the Cox regression model to quantify the preventive efficacy of oral insulin. RESULTS: Oral insulin reduced the frequency of T1D onset among participants with elevated IA-2A levels (HR 0.62; P = 0.012) but had no preventive effect among those with low IA-2A levels (HR 1.03; P = 0.91). High IA-2A levels were positively associated with the HLA DR4-DQ8 haplotype (OR 1.63; P = 6.37 × 10−6) and negatively associated with the HLA DR7– containing DRB1*07:01-DRB4*01:01-DQA1*02:01-DQB1*02:02 extended haplotype (OR 0.49; P = 0.037). Among DR4-DQ8 carriers, oral insulin delayed the progression toward stage 3 T1D onset (HR 0.59; P = 0.027), especially if participants also had high IA-2A level (HR 0.50; P = 0.028). CONCLUSIONS: These results suggest the presence of a T1D endotype characterized by HLA DR4-DQ8 and/or elevated IA-2A levels; for those patients with stage 1/2 disease with such an endotype, oral insulin delays the clinical T1D onset. [ABSTRACT FROM AUTHOR]

HVTN 505 is a preventative vaccine efficacy trial testing DNA followed by recombinant adenovirus serotype 5 (rAd5) in circumcised, Ad5-seronegative men and transgendered persons who have sex with men in the United States. Identified immune correlates of lower HIV-1 risk and a virus sieve analysis revealed that, despite lacking overall efficacy, vaccine-elicited responses exerted pressure on infecting HIV-1 viruses. To interrogate the mechanism of the antibody correlate of HIV-1 risk, we examined antigen-specific antibody recruitment of Fc[gamma] receptors (Fc[gamma]Rs), antibody-dependent cellular phagocytosis (ADCP), and the role of anti-envelope (anti-Env) IgG3. In a prespecified immune correlates analysis, antibody-dependent monocyte phagocytosis and antibody binding to Fc[gamma]RIIa correlated with decreased HIV-1 risk. Follow-up analyses revealed that anti-Env IgG3 breadth correlated with reduced HIV-1 risk, anti-Env IgA negatively modified infection risk by Fc effector functions, and that vaccine recipients with a specific Fc[gamma]RIIa single-nucleotide polymorphism locus had a stronger correlation with decreased HIV-1 risk when ADCP, Env-Fc[gamma]RIIa, and IgG3 binding were high. Additionally, Fc[gamma]RIIa engagement correlated with decreased viral load setpoint in vaccine recipients who acquired HIV-1. These data support a role for vaccine-elicited anti-HIV-1 Env IgG3, antibody engagement of FcRs, and phagocytosis as potential mechanisms for HIV-1 prevention., Introduction An efficacious vaccine that provides durable immunity remains a key priority in the fight against HIV-1. One strategy to identify an efficacious vaccine regimen is the identification of immune [...]

The gene complex located on chromosome 19q13.4 encodes the Killer‐cell Immunoglobulin‐like Receptors (KIRs), which exhibit remarkable polymorphism in both gene content and sequences. Further, the repertoire of KIR genes varies within and between populations, creating a diverse pool of KIR genotypes. This study was carried out to characterize KIR genotypes and haplotypes among 379 Arab Kuwaiti individuals including 60 subjects from 20 trio families, 49 hematopoietic cell transplantation (HCT) recipients and 270 healthy Kuwaiti volunteer HCT donors. KIR Genotyping was performed by a combination of reverse sequence specific oligonucleotide probes (rSSO) and/or Real Time PCR. The frequencies of KIR genes in 270 healthy Kuwaiti volunteer donors were compared to previously reported frequencies in other populations. In addition, we compared the differences in KIR repertoire of patients and healthy donors to investigate the reproducibility of previously reported significant differences between patients with hematological malignancies and healthy donors. The observed frequencies in our cohort volunteer HCT donors was comparable to those reported in neighboring Arab populations. The activating genes KIR2DS1, KIR2DS5 and KIR3DS1 and the inhibitory gene KIR2DL5 were significantly more frequent in patients compared to healthy donors, however, none of the previously reported differences were reproducible in our Kuwaiti cohort. This report is the first description of KIR gene carrier frequency and haplotype characterization in a fairly large cohort of the Kuwaiti population, which may have implications in KIR based HCT donor selection strategies. [ABSTRACT FROM AUTHOR]

The phase III RV144 HIV-1 vaccine trial estimated vaccine efficacy (VE) to be 31.2%. This trial demonstrated that the presence of HIV-1-specific IgG-binding Abs to envelope (Env) V1V2 inversely correlated with infection risk, while the presence of Env-specific plasma IgA Abs directly correlated with risk of HIV-1 infection. Moreover, Ab-dependent cellular cytotoxicity responses inversely correlated with risk of infection in vaccine recipients with low IgA; therefore, we hypothesized that vaccine-induced Fc receptor-mediated (FcR-mediated) Ab function is indicative of vaccine protection. We sequenced exons and surrounding areas of FcR-encoding genes and found one FCGR2C tag SNP (rs114945036) that associated with VE against HIV-1 subtype CRF01_AE, with lysine at position 169 (169K) in the V2 loop (CRF01_AE 169K). Individuals carrying CC in this SNP had an estimated VE of 15%, while individuals carrying CT or TT exhibited a VE of 91%. Furthermore, the rs114945036 SNP was highly associated with 3 other FCGR2CSNPs (rs138747765, rs78603008, and rs373013207). Env-specific IgG and IgG3 Abs, IgG avidity, and neutralizing Abs inversely correlated with CRF01_AE 169K HIV-1 infection risk in the CT- or TT carrying vaccine recipients only. These data suggest a potent role of Fc-γ receptors and Fc-mediated Ab function in conferring protection from transmission risk in the RV144 VE trial., Introduction The Thai phase III RV144 vaccine trial, which tested the ALVACHIV (vCP1521) prime and bivalent clade B/E recombinant gp120 boost vaccine regimen, showed an estimated vaccine efficacy (VE) of [...]

Objective: The purpose was to test the hypothesis that the HLA-DQαβ heterodimer structure is related to the progression of islet autoimmunity from asymptomatic to symptomatic type 1 diabetes (T1D).Research Design and Methods: Next-generation targeted sequencing was used to genotype HLA-DQA1-B1 class II genes in 670 subjects in the Diabetes Prevention Trial-Type 1 (DPT-1). Coding sequences were translated into DQ α- and β-chain amino acid residues and used in hierarchically organized haplotype (HOH) association analysis to identify motifs associated with diabetes onset.Results: The opposite diabetes risks were confirmed for HLA DQA1*03:01-B1*03:02 (hazard ratio [HR] 1.36; P = 2.01 ∗ 10-3) and DQA1*03:03-B1*03:01 (HR 0.62; P = 0.037). The HOH analysis uncovered residue -18β in the signal peptide and β57 in the β-chain to form six motifs. DQ*VA was associated with faster (HR 1.49; P = 6.36 ∗ 10-4) and DQ*AD with slower (HR 0.64; P = 0.020) progression to diabetes onset. VA/VA, representing DQA1*03:01-B1*03:02 (DQ8/8), had a greater HR of 1.98 (P = 2.80 ∗ 10-3). The DQ*VA motif was associated with both islet cell antibodies (P = 0.023) and insulin autoantibodies (IAAs) (P = 3.34 ∗ 10-3), while the DQ*AD motif was associated with a decreased IAA frequency (P = 0.015). Subjects with DQ*VA and DQ*AD experienced, respectively, increasing and decreasing trends of HbA1c levels throughout the follow-up.Conclusions: HLA-DQ structural motifs appear to modulate progression from islet autoimmunity to diabetes among at-risk relatives with islet autoantibodies. Residue -18β within the signal peptide may be related to levels of protein synthesis and β57 to stability of the peptide-DQab trimolecular complex. [ABSTRACT FROM AUTHOR]