Background:  Programmed death-1 (PD1) expression is related to the activation state of CD8⁺ cells and positively correlates with HIV viremia. A regulatory single nucleotide polymorphism (SNP) located in an enhancer within the fourth intron of the PD1 gene (PD1.3) has been associated with disease progression in various autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosis. PD1.3 (A allele) disrupts binding of the Runx1 transcription factor to the enhancer and thereby alters the regulation of PD1 gene expression. The aim of this study was to investigate PD1.3 genotype in patients initiating ART.

Methods:  Only patients naive to therapy and starting an efavirenz (EFV) -based regimen were included in the study (n = 77). The median viral load and CD4 count at baseline were 4.9 log₁₀ and 202 cells.mL^–1, respectively. Genomic DNA was extracted from whole blood and normalized to 20 ng.mL^–1. PD1.3 genotyping was carried out using a real-time allelic discrimination assay and CCR5 Δ32 genotyping by RFLP. PD1.3 and Δ32 genotype were then assessed for their influence on the time to virological suppression and differences in CD4 and CD8 counts (and percentage) from baseline to 8 months after initiation of therapy.

Results:  For PD1.3, 15 heterozygotes and 1 mutant homozygote were observed; for CCR5 Δ32, 7 heterozygotes were observed. Both SNP were in Hardy-Weinburg equilibrium. There were no associations (virological or immunological) with CCR5 Δ32 heterozygosity. Similarly, there were no associations with PD1.3 genotype at baseline. However, there was a trend in time to undetectable viral load between GG and GA individuals for PD1.3 (16 [8 to 16] vs 12 [8 to 16] weeks, respectively; p = 0.07). CD4 counts were significantly lower in GA than GG individuals at 2, 4, 6, and 8 months (eg, 240 [85 to 628] vs 379 [10 to 949], respectively, at 8 months; p = 0.009). There was no association with absolute CD8 counts, but a higher percentage of CD8 cells was observed in GA vs GG from 2 to 8 months (eg, 61 [38 to 77] vs 56 [17 to 83], respectively; p = 0.04).

Conclusions:  The PD-1 genotype is related to immunological progression in response to therapy. Although previous studies have shown that PD1 is a regulator of virus-specific CD8⁺ T-cell survival in HIV infection, further studies to characterize the impact on CD4⁺ cells are warranted.