The idea that herpes simplex virus type 1 (HSV-1) stokes the fires of Alzheimer’s disease has gained traction in recent years. If true, how would such a common infection trigger neurodegenerative disease in some people, but not others? A study published July 24 in the Journal of Immunology offers a potential explanation. Researchers led by Janardan Pandey of the Medical University of South Carolina and Hugo Lövheim of Umeå University in Sweden report that homozygous carriers of GM17—a variant of the IgG1 antibody gene—have a fourfold greater risk of AD. This common variant, it turns out, is deftly targeted by a decoy receptor HSV-1 expresses. This enables the virus to evade antibody-mediated host responses, i.e., immune defense. The researchers propose that the immune system’s loosened grip on HSV-1 could spur neurodegeneration.
- HSV-1 expresses a decoy receptor that thwarts host antibody responses, especially of the human IgG1 allele GM17.
- Homozygous GM17 carriers had fourfold increased risk of AD.
- GM17 associated with AD risk independently of ApoE or a polygenic risk score.
“These are very interesting results at both the levels of AD genetics and the potential infectious etiology of AD,” commented Rudolph Tanzi and William Eimer, both at Massachusetts General Hospital in Boston. “[The study] starts to address the recurring criticism that the penetrance of HSV-1 infection in the population does not correlate with incidence of AD pathology.”
The majority of the world’s population is infected with HSV-1. Most of the time, the virus is a latent lurker, but it can reactivate throughout life, triggering painful cold sores. The virus can even infect the CNS. Mounting evidence from epidemiological, neuropathological, and cell culture studies have gradually built a case that the virus could promote AD pathogenesis in some people (Jun 2018 news; May 2020 news; and for review, Marcocci et al., 2020).
More than a decade ago, Pandey, an infectious disease immunologist, hypothesized that whether the virus wreaks enough havoc to cause Alzheimer’s in a person could boil down to how well it evades his or her immune response (Pandey 2009). In particular, HSV-1 has evolved tricks to throw antibody-dependent cellular cytotoxicity off its scent. ADCC is an immune mechanism that wipes out infected cells. In ADCC, HSV-1 specific antibodies bind to infected cells with their Fab regions, tagging them for destruction by innate immune cells such as macrophages. These killer cells latch onto their antibody-bound prey via Fcγ receptors (FcγRs). To counteract this process, HSV-1 produces decoy FcγRs, which bind to the antibodies and block their association with effector cells (Frank et al., 1989; Sprague et al., 2006; Lubinski et al., 2011). Importantly, these decoy receptors latch on to a specific variant, also called an allotype, of IgG1 heavy chain—γ marker (GM)17—more strongly than they bind other antibody types (Atherton et al., 2000).
Might their hobbled defense against HSV-1 put homozygous carriers of GM17 at higher risk of AD? To chip away at the answer, Pandey and colleagues genotyped 363 AD cases and 363 age-matched controls for GM17 and GM3, the two possible IgG1 variants at this position in the gene. The samples came from the Northern Sweden Health and Disease Study, a nested case-control study in which samples from people who later developed AD were paired with samples from controls. Lövheim had previously reported that HSV-1 infection synergized with genetic risk factors, including ApoE4, in upping AD risk in this cohort, and Pandey initiated a collaboration with Lövheim to investigate a linkage between GM17 allotype and AD risk (Lopatko Lindman et al., 2019).
In this series, GM17/17 homozygotes were more prevalent among AD cases than among controls, appearing in 19.8 and 10.7 percent of the samples, respectively. The opposite was true for GM3/3 homozygotes, which represented 33.1 percent of cases and 41.3 percent of controls.
The researchers found that GM17/17 came with a fourfold increased risk of AD, independent of ApoE genotype. While ApoE4 and GM17/17 both increased AD risk, the two factors did not appear to synergize to further crank up risk in people who carried both. This held true when the researchers factored in a polygenic risk score— based on genotypes at nine known AD risk loci—that they had previously tied to AD risk.
Together, the findings suggest that GM17/17 carriers face higher odds of developing AD. How might this relate to HSV-1’s immune-evasion strategies? The scientists detected anti-HSV-1 IgG antibodies—a proxy for infection with the virus— in about 90 percent of AD cases as well as controls. However, levels of these IgG antibodies were lower in people with two copies of GM17, in keeping with the idea that scavenging by viral decoy receptors enhanced GM17 internalization by infected cells (Ndjamen et al., 2014). While the GM17/17 genotype associated with lower HSV-1-specific IgG antibodies in the serum, ApoE4 carriers had higher levels of IgM antibodies against the virus. IgM antibodies predominate at the beginning of an immune response, hence their presence suggests a recent reactivation of the virus. Taken together, the findings suggest to the authors that GM17/17 and ApoE may influence immunity against HSV-1 via distinct mechanisms, both of which could potentially sway a person’s Alzheimer’s risk.
Lövheim told Alzforum that while HSV-1 immunoevasion is the most likely explanation for the link between GM17 and AD risk, it’s possible that the allele works via other mechanisms. For example, GM alleles could differentially influence antibody-mediated uptake of Aβ by microglia. Tanzi and Eimer noted that HSV-1 is not the only pathogen that has an FcγR decoy up its sleeves. “Human cytomegalovirus glycoprotein 34 and Staphylococcus aureus protein A both promote immune suppression during infection and bind to the same FcγR, suggesting that other pathogens should also be explored for their potential roles in AD etiology,” they wrote.
Even if HSV-1 is the culprit, the data do not prove that a weakened antibody response against the virus would promote its entry into the brain and/or influence AD pathogenesis. The authors proposed a deeper investigation into potential mechanisms, and that the genetic studies should be replicated in large, multiethnic cohorts.
Why hasn’t GM17 popped up in larger genome-wide association studies before? IgG genes are multiallelic and highly homologous, making them difficult to genotype. As such, single-nucleotide polymorphisms that distinguish between GM3 and GM17 are not included on the genotyping chips used in AD GWAS. AD geneticists contacted by Alzforum confirmed that the SNP in question— rs1071803—was not included in the largest recent AD GWAS (Calonga-Solís et al., 2019; Jansen et al., 2019). However, they also noted that another nearby SNP—rs12147642— is in high linkage disequilibrium with the GM3,17 SNP, and it was not tied to AD risk. According to an NIH LD pairing tool, the two SNPs have a 94 percent chance of co-inheritance (R2=0.94). The authors noted the possibility that other GM allotypes in high linkage disequilibrium with the GM3,17 alleles, such as GM1 and GM21 alleles within the IGHG1 and IGHG3 genes, respectively, may have been responsible for the link to AD risk.
GM3,17 alleles of IgG1 have not been directly tested in any AD GWAS. That said, one large GWAS has tied variants near the immunoglobulin heavy chain variable (IGHV) locus to the disease (Witoelar et al., 2018). Rare variants in the IGHG3 gene, which encodes the constant region of IgG3, have emerged in whole-exome sequencing studies (Aug 2018 news).—Jessica Shugart
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