Polymorphisms in IFNγ and IL-19 Genes Inhibit CD4 Recovery

Polymorphisms could represent markers of immunodiscordant response in patients with HIV starting combination antiretroviral therapy (cART) with CD4 T cells <200 cells/µL, according to study results published in the Journal of Antiviral Research.

In most patients with HIV, cART is able to block viral replication, resulting in undetectable HIV levels and immune reconstitution. However, despite successful viral suppression with cART some patients continue to present with low increases in CD4 T cells; these patients are referred to as immunologic nonresponders. As a result of the increasing percentage of patients with delayed diagnosis, the immunologic nonresponders phenotype implies a greater probability of impaired CD4 T cell recovery, which is associated with an increased risk of experiencing AIDS and non-AIDS clinical events.

Single nucleotide polymorphisms (SNPs) in genes related to proliferation, survival, and apoptosis pathways have previously demonstrated an association with CD4 T cell recovery with cART. One of these is an SNP in interleukin-15 (IL-15), a cytokine associated with increased CD4 T cell counts during cART and SNPs in interferon gamma (IFNg) and IL-19 cytokines that could affect CD4 T cell increase after cART. However, the possible association between genetic variants in these cytokines and the immunodiscordant phenotype remains to be explored. Therefore, this retrospective study evaluated the association between polymorphisms in cytokines involved in immune response (IL15, IFNg AA genotype, and IL-19 TT genotype) and the failure to achieve optimal CD4 T cell restoration after cART.

A total of 412 samples from patients with HIV starting cART with CD4 <200 cells/µL were included in the study. Patients were stratified into 1 of 2 groups based on their increase in CD4 level. If a patient had a CD4 <200 cells/µL after 2 years on successful cART, they were classified as immunologic nonresponders; if patients had a CD4 increase ³200 cells/µL, they were classified as immunologic responders.

Polymorphisms rs1493013 IL-15, rs2430561 IFNg, and rs2243191 IL-19 were selected based on a minimum allele frequency higher than 5% in Utah residents with ancestry from Northern and Western Europe and Tuscany, Italy, from 1000 genomes project data. These SNPs were genotyped using Sequinom’s MassARRAY^® (Agena Bioscience, San Diego, California) platform. The primary outcome variable was the increase in CD4 count after 2 years on successful cART.

Results showed that polymorphisms in IFNg and IL-19 genes significantly affected the probability of suboptimal immune recovery. After 2 years of successful cART, 134 patients (32%) were classified as immunologic nonresponders with a median CD4 increase of 133 cells/µL, while the remaining 278 patients (68%) achieved an increase in CD4 ³200 cells/µL and were classified as immunologic responders (P <.001). When comparing immunologic nonresponders and immunologic responders, significant changes were observed: immunologic nonresponders patients were older (P =.009), presented a slightly longer duration of HIV infection (P =.029), and showed a higher prevalence of injected drug user (P =.003) compared with patients who were immunologic responders.

Further, in a multivariate analysis adjusted for factors such as age, sex, infection route, ethnic origin, hepatitis co-infection, and HIV infection length, the AA genotype of a SNP in IFNg and the TT genotype of a SNP in IL-19 showed a significant association with immunologic nonresponders (P =.017 and P =.019, respectively). These results suggest that SNPs could potentially represent predictive markers of immunodiscordant response in patients with HIV who start cART with CD4 T cells <200 cells/µL.

Overall, the study authors concluded that, “Thus, these results represent an important progress in the understanding of factors underlying the phenomenon of poor CD4 restoration in this special population of patients, a population that has substantially increased in the last years due to the increasing rate of late presenters among the new HIV diagnoses.”

Reference

Garcia M, Jimenez-Sousa MA, Blanco J, et al. CD4 recovery is associated with genetic variation in IFNg and IL19 genes [published online August 3, 2019]. Antiviral Research. doi:10.1016/j.antiviral.2019.104577