Significance of minority HIV-1 X-4-tropic variants, Host CCR5 promoter genotype in predicting paediatric Virological failure

Abstract

Background By Sept 2018, only 59.3% of all HIV positive children on cART under 5 years were achieving virological suppression compared to 88.4% in the general population in Uganda. However, while its known that a tropism switch from R5 to X4-tropic viruses and genetic variations in the CCR5 promoter correlate with viremia and accelerated HIV disease progression. The association has not been explored taking into account minor X4-tropic variants and novel CCR5 promoter sequence analysis among HIV-1 seropositive infants on cART in Uganda. This study utilized the sensitivity of next-generation sequencing and standard Sanger genotyping to fill the gap. Methods Following IRB approval from Makerere University School of Biomedical Sciences-IRB, buffy coat and plasma samples belonging to HIV-1 seropositive infants in the DRIBS study at Joint Clinical Research Centre - Kampala were genotyped for host CCR5 promoter polymorphisms and prospectively tested for viral tropism at baseline and six months after enrolment using Sanger and next-generation sequencing respectively. Logistic regression was performed to see the association of CCR5 promoter polymorphisms and infant virological failure in GraphPad Prism v 8.0.2. Results 11 of 14 (78.57%) infants were virologically failing at six months and only 3 (21.43%) were suppressing. Paired analyses showed no significant drops in viral load and increases in CD4+ T cell count at 6 months respectively (P 0.0842 and 0.5210). A total of 14 SNPs were observed, 10 previously reported and 4 (58227G/GA, 58636A/AG, 59802A/AC, and 60024A/AG) are novel. SNPs 59402G/A (77.8%) was most observed while 59402G/GA (22.2%) was least frequent. Although, SNPs 58636A/AG, 58934T/G and 59402G/A showed relatively higher odds ratios among viremics, SNPs were not associated with virological failure among infants at six months (p-value > 0.05). Closer analysis of the two novel SNPs 59802A/AC, and 60024A/AG reveals a linkage disequilibrium between the two. Conclusion There was no association of CCR5 promoter polymorphisms and virological failure among HIV seropositive infants on cART. However, studies with larger samples sizes and appropriate control groups should be conducted to improve the statistical power of these findings.