P08-04. The role of class I HLA-B and HLA-Cw in disease progression and maternal-infant HIV-1 transmission in a South African population

Background: Human leukocyte antigens play an integral role in the cytotoxic T-cell pathway and serve as ligands for natural killer cell receptors. We have investigated the role of two HLA class I; genes on disease progression and maternal-infant HIV-1 transmission using 222 South African mother-infant pairs recruited as part of a mother-to-infant HIV-1 transmission study. Methods: High resolution genotyping of HLA class I; B and Cw loci was performed using a sequence-based typing strategy and alleles were collapsed to a four-digit assignment for purpose of analysis. Results: B*5802 and Cw*0602 were significantly associated with high viral load (VL) (P = 0.038 and P = 0.017 respectively) and low CD4 count (P < 0.001 and P = 0.005 respectively). These two alleles are in linkage disequilibrium (D' = 1.00; P < 0.001) and the most prevalent haplotype amongst Black South Africans (f = 9.94%). The B*5802-Cw*0602 haplotype was also significantly associated with low CD4 count (P = 0.001) and showed a trend with high VL (P = 0.073). Furthermore, B*4501 showed a trend with high VL (P = 0.086) and low CD4 count (P = 0.062). B*4201 was significantly associated with low VL (P = 0.045) and another prevalent haplotype, B*4201-Cw*1701 (f = 9.65%), was significantly associated with low VL (P = 0.049). The Cw allotype groups (C1&C2) showed no significant association with markers of disease severity, whereas, contrary to other studies, Bw4/Bw4 homozygosity was significantly associated with high VL (P = 0.038) and low CD4 count (P = 0.015). B*0801 showed a trend (P = 0.064) of lower representation amongst infected infants compared to exposed uninfected infants. Transmitting mothers had significantly higher representation of B*1402 (P = 0.034) and a trend of lower representation of B*4201 (P = 0.082) compared to non-transmitting mothers. No Cw* alleles or allotype groups showed significant association with HIV-1 transmission. Conclusion: This study highlights the different roles played by HLA in disease progression and maternal-infant HIV-1 transmission and also serves as a basis for future work that will study the role of KIR-HLA in the same contexts

Cardiac and Pulmonary Dosimetric Parameters in Lung Cancer Patients Undergoing Post-Operative Radiation Therapy in the Real-World Setting

Purpose/Objective(s): The recently published Lung ART trial reported increased rates of cardiac and pulmonary toxicity in the post-operative radiation therapy arm. It remains unknown whether the dosimetric parameters reported in Lung ART are representative of real-world practice. The purpose of this study is to examine heart and lung dose exposure in patients receiving post-operative radiation therapy for non-small cell lung cancer (NSCLC) across a statewide consortium. Materials/Methods: From 2012 to 2020, 377 patients at 27 academic and community centers within the Michigan Radiation Oncology Quality Consortium (MROQC) underwent surgical resection followed by post-operative radiation therapy for non-metastatic NSCLC. Demographic and dosimetric data were prospectively collected for these patients. Rates of 3D-CRT and IMRT use were analyzed. Mean heart dose (MHD), heart V5, heart V35, mean lung dose (MLD), lung V20, target volume and minimum dose to 95% PTV were calculated for these patients and the reported dosimetric parameters were stratified by treatment modality. Results: 51% of patients in this cohort had N2 disease at the time of surgery, 18% had a positive margin. 65.8% of patients were treated with IMRT compared to 32.1% treated with 3D-CRT. Average MHD for all patients was 10.3 Gy, mean Heart V5 was 40.3% and mean heart V35 was 12.6%. Average MLD was 11.2 Gy and mean lung V20 was 18.9%. These dosimetric parameters did not significantly differ based on treatment modality, with MHD and MLD 9.9 Gy and 10.1 Gy, respectively, for patients treated with 3D-CRT compared to 10.6 Gy and 11.8 Gy for patients treated with IMRT. Conclusion: Cardiac and lung dosimetric parameters for patients receiving post-operative radiation therapy for NSCLC are similar to the dosimetric characteristics reported in Lung ART. The mean heart and mean lung doses observed are slightly lower (MHD 10.3 Gy, MLD 11.2 Gy) compared to Lung ART (MHD 13 Gy, MLD 13 Gy), possibly owing to increased use of IMRT. These data support application of Lung ART\u27s findings outside of the clinical trial setting

Killer-cell immunoglobulin-like receptor genotyping and HLA killer-cell immunoglobulin-like receptor-ligand identification by real-time polymerase chain reaction.

The effector function of natural killer (NK) cells is modulated by surface expression of a range of killer-cell immunoglobulin-like receptors (KIRs) that interact with human leukocyte antigen (HLA) class I ligands. We describe the use of real-time polymerase chain reaction (PCR) assays that allow easy and quick detection of 16 KIR genes and the presence/absence of KIR-ligands based on allelic discrimination at codon 80 in the HLA-A/B Bw4 and HLA-C C1/C2 genes. These methods overcome the tedious and expensive nature of conventional KIR genotyping and HLA class I typing using sequence-specific primer (SSP) PCR, sequence-specific oligonucleotide (SSO) hybridization or sequence-based typing (SBT). Using these two cost-effective assays, we measured the frequencies of KIRs, KIR-ligands and KIR/KIR-ligand pairs in a cohort of Black women recruited in South Africa

A unique perinatally HIV-infected child with long-term sustained virological control following antiretroviral treatment cessation

Understanding HIV remission in rare individuals who initiated antiretroviral therapy (ART) soon after infection and then discontinued, may inform HIV cure interventions. Here we describe features of virus and host of a perinatally HIV-1 infected child with long-term sustained virological control. The child received early limited ART in the Children with HIV Early antiRetroviral therapy (CHER) trial. At age 9.5 years, diagnostic tests for HIV are negative and the child has characteristics similar to uninfected children that include a high CD4:CD8 ratio, low T cell activation and low CCR5 expression. Virus persistence (HIV-1 DNA and plasma RNA) is confirmed with sensitive methods, but replication-competent virus is not detected. The child has weak HIV-specific antibody and T cell responses. Furthermore, we determine his HLA and KIR genotypes. This case aids in understanding post-treatment control and may help design of future intervention strategies

Genome-Wide Association Study Identifies Novel Colony Stimulating Factor 1 Locus Conferring Susceptibility to Cryptococcosis in Human Immunodeficiency Virus-Infected South Africans.

Background: Cryptococcus is the most common cause of meningitis in human immunodeficiency virus (HIV)-infected Africans. Despite universal exposure, only 5%-10% of patients with HIV/acquired immune deficiency syndrome and profound CD4+ T-cell depletion develop disseminated cryptococcosis: host genetic factors may play a role. Prior targeted immunogenetic studies in cryptococcosis have comprised few Africans. Methods: We analyzed genome-wide single-nucleotide polymorphism (SNP) genotype data from 524 patients of African descent: 243 cases (advanced HIV with cryptococcal antigenemia and/or cryptococcal meningitis) and 281 controls (advanced HIV, no history of cryptococcosis, negative serum cryptococcal antigen). Results: Six loci upstream of the colony-stimulating factor 1 (CSF1) gene, encoding macrophage colony-stimulating factor (M-CSF) were associated with susceptibility to cryptococcosis at P < 10-6 and remained significantly associated in a second South African cohort (83 cases; 128 controls). Meta-analysis of the genotyped CSF1 SNP rs1999713 showed an odds ratio for cryptococcosis susceptibility of 0.53 (95% confidence interval, 0.42-0.66; P = 5.96 × 10-8). Ex vivo functional validation and transcriptomic studies confirmed the importance of macrophage activation by M-CSF in host defence against Cryptococcus in HIV-infected patients and healthy, ethnically matched controls. Conclusions: This first genome-wide association study of susceptibility to cryptococcosis has identified novel and immunologically relevant susceptibility loci, which may help define novel strategies for prevention or immunotherapy of HIV-associated cryptococcal meningitis

Human leukocyte antigen class I (A, B, C) and II (DRB1) diversity in the black and Caucasian South African population

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