Work

Relationship of Genotype for HLA B*57 and IFNL4 With Disease Progression in Female HIV Controllers

Year: 2017

Type: letter

Abstract: To the Editor—Dominguez-Molina et al [1] identified genetic associations of the HLA-B*57 allele group and interferon lambda 4 (IFNL4)–ΔG/TT genotype (rs368234815; formerly designated ss469415590) with CD4 T-cell decline in human immunodeficiency virus (HIV) controllers. To examine these associations in the Women’s Interagency HIV Study (WIHS), we identified HIV-infected women (n = 178) with complete data for those genetic loci and the HIV controller phenotype. We defined this phenotype, per the International HIV Controllers Study [2], as ≥3 consecutive measurements of plasma virus load (VL) <2000 RNA copies/mL over a period of ≥12 months in the absence of antiretroviral therapy (ART). Genotyping and imputation methods for HLA-B and IFNL4-ΔG/TT in WIHS have been described elsewhere [3, 4]. The median age at enrollment for WIHS controllers was 36 years (interquartile range, 30–42 years) and most participants (n = 116; 65%) were African American (32 Hispanic, 24 white, 6 other). The median follow-up time was 14 years (range, 2–21). Fifty-one controllers (29%) never started ART. Controllers who did start ART did so after a wide range of follow-up time (median, 6 years; range, 1–20 years) and at a wide range of CD4 T-cell counts (median T-cell count, 396/µL; range, 12–973/µL). To replicate the HIV progression phenotype used by Dominguez-Molina et al [1] (“subjects with CD4+ T-cell counts >500 cells/mm3 for >7 years after HIV diagnosis”), we studied the subset of WIHS HIV controllers (n = 145; 81%) who had been followed up for ≥7 years. Of these, 19 (13%) always had a CD4 T-cell count >500/mm3 (>500/µL) and could be defined as long-term nonprogressors (LTNPs). In bivariate analysis (Table 1), we observed a significant positive association of the B*57 allele group with the LTNP phenotype among WIHS controllers (odds ratio [OR], 4.2; exact 95% confidence interval [CI], 1.4–13.1; P = .006), which remained significant after adjustment for age and race/ethnicity (adjusted OR, 6.0; exact 95% CI, 1.9–20.3; P = .002) in multivariable logistic regression analysis. We found no significant association between IFNL4-ΔG/TT genotype and being a LTNP among WIHS controllers (adjusted OR, 1.6; exact 95% CI, 0.4–5.6; P = .63). Genetic Associations With the LTNP Phenotype in WIHS HIV Controllers (n = 145)a Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; LTNP: long-term nonprogressor; NE, not estimable; OR, odds ratio; WIHS, Women’s Interagency HIV Study. aThe LTNP phenotype was defined as all CD4 T-cell counts >500/mm3 (>500/µL) in women with ≥7 years of follow-up. bAdjusted for age at enrollment and race/ethnicity (African American, Hispanic, white, or other) cAs in the study by Dominguez-Molina et al [1], the IFNL4-ΔG/TT genotype was analyzed as IFNL4-TT/TT vs IFNL4-TT/ΔG and IFNL4-ΔG/ΔG. Genetic Associations With the LTNP Phenotype in WIHS HIV Controllers (n = 145)a Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; LTNP: long-term nonprogressor; NE, not estimable; OR, odds ratio; WIHS, Women’s Interagency HIV Study. aThe LTNP phenotype was defined as all CD4 T-cell counts >500/mm3 (>500/µL) in women with ≥7 years of follow-up. bAdjusted for age at enrollment and race/ethnicity (African American, Hispanic, white, or other) cAs in the study by Dominguez-Molina et al [1], the IFNL4-ΔG/TT genotype was analyzed as IFNL4-TT/TT vs IFNL4-TT/ΔG and IFNL4-ΔG/ΔG. Our data replicate the influence of HLA-B on CD4 T-cell counts in HIV controllers; however, no association of IFNL4-ΔG/TT genotype with the LTNP phenotype was observed. The number of HIV controllers with LTNP in WIHS is not large; therefore, our statistical power to assess IFNL4-ΔG/TT genotype was relatively low. In addition, WIHS participants differ from the populations studied by Dominguez-Molina et al [1] in at least 2 important ways. First, most WIHS controllers were African American, whereas the previous study was restricted to patients of European ancestry. However, given that IFNL4-ΔG/TT is a functional variant, rather than simply a genetic marker, it is not obvious why an association between IFNL4-ΔG/TT genotype and CD4 T-cell loss would not be seen across ancestral groups. The study populations also differ with regard to sex: WIHS is restricted to women, whereas the populations studied by Dominguez-Molina et al are mostly male. The authors might examine whether the association of IFNL4-ΔG/TT genotype with CD4 T-cell loss among HIV controllers differs between men and women, because sex differences in IFNL4-ΔG/TT genotype associations with liver fibrosis have been observed [5]. Disclaimer. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health or the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. Financial support. This work was supported in part by the National Institutes of Health (grants R01AI057006 and R01CA085178 to H. D. S.) and the Intramural Research Program of the National Institutes of Health (National Cancer Institute, Division of Cancer Epidemiology and Genetics). Additional data were collected by the University of Alabama-Mississippi WIHS (principal investigators, Michael Saag, Mirjam-Colette Kempf, and Deborah Konkle-Parker; grant U01-AI-103401); Atlanta WIHS (Ighovwerha Ofotokun and Gina Wingood; grant U01-AI-103408; Bronx WIHS (Kathryn Anastos; U01-AI-035004); Brooklyn WIHS (Howard Minkoff and Deborah Gustafson; grant U01-AI-031834); Chicago WIHS (Mardge Cohen and Audrey French; grant U01-AI-034993); Metropolitan Washington WIHS (Seble Kassaye; grant U01-AI-034994); Miami WIHS (Margaret Fischl and Lisa Metsch; grant U01-AI-103397); University of North Carolina WIHS (Adaora Adimora; grant U01-AI-103390); Connie Wofsy Women’s HIV Study, Northern California (Ruth Greenblatt, Bradley Aouizerat, and Phyllis Tien; grant U01-AI-034989); WIHS Data Management and Analysis Center (Stephen Gange and Elizabeth Golub; grant U01-AI-042590; and Southern California WIHS (Joel Milam; grant U01-HD-032632) (WIHS I–WIHS IV). All grants are from NIH. The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases, with additional cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Mental Health. Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research, the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Deafness and other Communication Disorders, and the NIH Office of Research on Women’s Health. WIHS data collection is also supported by grants UL1-TR000004 to University of California San Francisco Clinical and Translational Science Award (CTSA) and UL1-TR000454 to Atlanta CTSA. Potential conflicts of interest. L. P. O and T. R. O. are inventors on patent applications filed by the National Cancer Institute for the IFNL4-ΔG/TT (rs368234815) genotype-based test. All other authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Source: Clinical Infectious Diseases

DOI: 10.1093/cid/cix481

Authors: Mark H Kuniholm, Howard D Strickler, Kathryn Anastos, Ludmila Prokunina-Olsson, Bradley E Aouizerat, Thomas R O’Brien