Association of Dementia Human Leukocyte Antigen (HLA) Profile with Human Herpes Viruses 3 and 7: An in silico Investigation

Abstract

Human leukocyte antigen (HLA), the most highly polymorphic region of the human genome, is increasingly recognized as an important genetic contributor to dementia risk and resilience. HLA is involved in protection against foreign antigens including human herpes viruses (HHV), which have been widely implicated in dementia. Here we used an in silico approach¹ to determine binding affinities of glycoproteins from 9 human herpes virus (HHV) strains to 113 HLA alleles, and to examine the association of a previously identified HLA-dementia risk profile² to those affinities. We found a highly significant correlation between high binding affinities of HLA alleles to HHV 3 and 7 and the dementia risk scores of those alleles, such that the higher the estimated binding affinity, the lower the dementia risk score. These findings suggest that protection conferred by HLA alleles may be related to their ability to bind and eliminate HHV3 and HHV7 and point to the possibility that protection against these viruses may reduce dementia incidence.

Figure 1.

The sliding-window testing method is illustrated for 9-mers, as applied to the envelope glycoprotein H amino acid sequence of HHV7 to investigate binding affinities to HLA Class I molecules. Capital case letters in the sequence denote a specific amino acid residue. Brown horizontal lines indicate four 9-mer subsequences obtained by shifting the sliding window by one amino acid residue at a time.

Figure 2.

The sliding-window testing method is illustrated for 22-mers, as applied to the envelope glycoprotein H amino acid sequence of HHV7 to investigate binding affinities to HLA Class II molecules. Capital case letters in the sequence denote a specific amino acid residue. Brown horizontal lines indicate four 22-mer subsequences obtained by shifting the sliding window by one amino acid residue at a time.

Figure 3.

Frequency distribution of the dementia risk scores of the 113 alleles used (Table 2).

Figure 4.

Frequency distribution of APR<1 values (N = 752 of a total of 9 HHV strains × 113 HLA alleles = 107 values; the remainder had values of APR≥1).

Figure 5.

Scatter plots of dementia risk scores against APR<1 values for the each HHV strain. A statistically significant correlation was found only for HHV3 (r = 0.260, P = 0.013, N = 91) and HHV7 (r = 0.287, P = 0.008, N = 85). All correlations and associated statistics are given in Table 3.

Figure 6.

Scatter plot of dementia risk scores against APR<1 values for the pooled data of HHV3 and HHV7 (r = 0.270, P = 0.00029, N = 176).