A glycan shield on chimpanzee CD4 protects against infection by primate lentiviruses (HIV/SIV)

Abstract

Pandemic HIV-1 (group M) emerged following the cross-species transmission of a simian immunodeficiency virus from chimpanzees (SIVcpz) to humans. Primate lentiviruses (HIV/SIV) require the T cell receptor CD4 to enter into target cells. By surveying the sequence and function of CD4 in 50 chimpanzee individuals, we find that all chimpanzee CD4 alleles encode a fixed, chimpanzeespecific substitution (34T) that creates a glycosylation site on the virus binding surface of the CD4 receptor. Additionally, a single nucleotide polymorphism (SNP) has arisen in chimpanzee CD4 (68T) that creates a second glycosylation site on the same virusbinding interface. This substitution is not yet fixed, but instead alleles containing this SNP are still circulating within chimpanzee populations. Thus, all allelic versions of chimpanzee CD4 are singly glycosylated at the virus binding surface, and some allelic versions are doubly glycosylated. Doubly glycosylated forms of chimpanzee CD4 reduce HIV-1 and SIVcpz infection by as much as two orders of magnitude. Full restoration of virus infection in cells bearing chimpanzee CD4 requires reversion of both threonines at sites 34 and 68, destroying both of the glycosylation sites, suggesting that the effects of the glycans are additive. Differentially glycosylated CD4 receptors were biochemically purified and used in neutralization assays and microscale thermophoresis to show that the glycans on chimpanzee CD4 reduce binding affinity with the lentiviral surface glycoprotein, Env. These glycans create a shield that protects CD4 from being engaged by viruses, demonstrating a powerful form of host resistance against deadly primate lentiviruses. arms race | virus entry | population genetics | selection

CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses

“…2 A ). This PNGS, which has been experimentally confirmed to be glycosylated ( 61 ), appears to occupy a similar structural position as the chimpanzee glycan at position 66, which is known to interfere with SIV Env binding ( 55 ). To examine whether N15 has a protective effect, we changed the asparagine at position 15 in one representative gorilla CD4 allele (AHSM) to a threonine, which is present in all other African primates.…”

Evolutionary Arms Race between Virus and Host Drives Genetic Diversity in Bat Severe Acute Respiratory Syndrome-Related Coronavirus Spike Genes

“…An increasing number of studies have suggested that coevolution is driven by specific interactions between high levels of virus sequence divergence and polymorphic host receptors (40,41,(43)(44)(45)(46). The first example was observed for the avian leucosis virus infection, in which receptor polymorphism in chicken could alter the sensitivity to virus entry (44).…”

Evolution of pathogen tolerance and emerging infections: A missing experimental paradigm

“…Levels of pathogen sequence divergence can further accelerate with increased polymorphism of host receptors (Gupta et al, 2009;Meyerson and Sawyer, 2011;Warren et al, 2019), allowing pathogens to infect and adapt to another host more effectively (Daugherty and Malik, 2012). For instance, a recent study that analysed ACE2 receptors in Chinese Horseshoe bats (Rhinolophus sinicus) found multiple such highly polymorphic sites in the receptor regions which interacts with the spike proteins of SARSr-CoV, coronavirus isolated from the same species of bats (Guo et al, 2020).…”