Simian Arterivirus Causing Fatal Hemorrhagic Fevers Acquired Mutations Needed to Transition to Humans

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A new U.S. NIH sponsored study has shockingly found that a primate hemorrhagic fever-causing arterivirus from Africa has acquired the necessary mutations to cross over into the human species using the CD162 receptors for cellular entry.

The study findings were published in the peer reviewed journal: Cell.
https://www.cell.com/cell/fulltext/S0092-8674(22)01194-1

Simian hemorrhagic fever is a lethal disease that has been documented in captive Asian macaques (Macaca spp.). Outbreaks have occurred in macaque colonies worldwide (Figure 1A) and have been traced to at least three different simian viruses (Figure 1B, in red) classified in subfamily Simarterivirinae (Nidovirales: Arteriviridae) (Kuhn et al., 2016; Lauck et al., 2015).

These simian arteriviruses likely entered primate facilities through the import of subclinically infected wild African monkeys. To date, primate facilities remain vigilant about preventing exposure to these viruses (Johnson et al., 2011; Lauck et al., 2015).

Human infections at affected primate facilities have not been detected. Further, there is no way to surveil for prior human exposure in Africa, where these viruses are endemic in primates, because no serology tests exist.

In the absence of strong biological indications that humans could be at risk of infection with these viruses, there has been little impetus to interrogate the interface between nonhuman primates and humans in Africa to exclude cryptic spillover events or subclinical infection cycles.

Figure 1 – Historical outbreaks and natural reservoirs for simian arteriviruses – (A) Documented simian arterivirus disease outbreaks in primate facilities. Locations of affected facilities are shown by colored circles on the map and timeline. Several facilities experienced multiple outbreaks.
(B) Phylogeny of representative viruses within the order Nidovirales, including all published simian arteriviruses, based on an alignment of concatenated RNA-directed RNA polymerase (RdRp) and helicase genes. Arteriviruses known to have caused outbreaks in primate facilities are written in red. The tree is drawn to scale, with branch lengths measured in the number of substitutions per site and bootstrap values shown for major nodes. Asterisks indicate nodes with 100% support.
(C) Geographical ranges of species of primates known to be infected with simian arteriviruses. Sampling sites are indicated by black stars. ∗Only detected in captivity; †Kafue kinda chacma baboon virus (KKCBV) was discovered in kinda × chacma hybrid baboons, within Kafue National Park, as shown as an inset in red (Chiou et al., 2021).

The result of the study ….

We identified CD163 as the intracellular receptor for a primate arterivirus, SHFV. The expression of CD163 is restricted to myeloid cells such as monocytes and macrophages, where it plays an important role in human health (Greaves and Gordon, 2005). When hemoglobin is released into plasma during red blood cell destruction, it is important that it is quickly removed due to the toxicity of its oxidative heme group.

Tissue-embedded macrophages take care of this important process, primarily through their CD163 receptor (Kristiansen et al., 2001). Other mammalian arteriviruses have also been associated with CD163 and with tissue-resident monocytes and macrophages (Calvert et al., 2007; Gorp et al., 2010; Huang et al., 2020; Su et al., 2021; Xu et al., 2020; Yu et al., 2020). CD163 is mostly localized intracellularly (Gorp et al., 2009; Nielsen et al., 2006), a common feature shared with many endocytic receptors that traffic between the cell surface and endosomes.

Intracellular processing of the SHFV glycoprotein(s) may be required before CD163 receptor binding can occur. Neutralization experiments utilizing purified soluble grivet CD163 did not prevent SHFV infection (data not shown). This lack of neutralization suggests that arteriviruses, as they circulate in the bloodstream, cannot bind CD163. Instead, we speculate that the unmasking of CD163 binding sites occurs within intracellular compartments.

This may function as a mechanism to evade the humoral immune response, as has also been speculated for Ebola virus (Miller et al., 2012), and would be consistent with the observation of persistent arterivirus infections in monkeys (Bailey et al., 2014a, Bailey et al., 2014b). This finding has important consequences that need to be prospectively considered in risk scenarios: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which like SHFV is also a nidovirus, in contrast uses a receptor on the cellular surface (ACE2) for cell entry.

To do so, SARS-CoV-2 needs to expose its receptor-binding domain prior to adsorbing to cells, thereby leaving it exposed to attack by neutralizing antibodies – the basis for current vaccine approaches. Viruses that use intracellular receptors expose their receptor-binding domains only once inside a cellular compartment.

Thus, medical countermeasure development against such viruses is challenging, i.e., strategies that have been successful against SARS-CoV-2 may fail against arteriviruses.

Arteriviruses have been considered relatively obscure since their discovery. However, it should be noted that SIV, and in particular the chimpanzee variant most closely related to the pandemic strain of HIV, was also considered an “obscure” virus prior to its discovery in the early years of the HIV/AIDS pandemic (Keele et al., 2006; Sharp and Hahn, 2011). Given the propensity for RNA viruses such as SHFV and SIV to evolve and emerge, ignoring the threat that arteriviruses pose could be unwise.

Our results raise concerns for global health and pandemic prevention. Not only is the human CD163 ortholog compatible with SHFV entry into human cells, but all other cellular proteins required for SHFV replication are functional in human cells, as evidenced by SHFV titers of up to 107 infectious virions per mL (Figure 6C).

Further, we have tested only one of the numerous simian arteriviruses that have been discovered in monkeys (Bailey et al., 2014a, Bailey et al., 2016; Lauck et al., 2011, Lauck et al., 2013, Lauck et al., 2015). They all share the same genetic organization and considerable sequence homology, suggesting that all of them use a similar entry mechanism and that many of them could potentially use human CD163.

Further, it appears that interferon-mediated pathways of innate immunity may be ineffective at blocking these viruses, which is concerning given that humans are predicted to be antibody-naive to arteriviruses. Animal studies are not needed before concern for humans is raised, because at least three different simian arteriviruses have already been shown (on numerous occasions) to cause fatal infection in some nonhuman primates.

It is possible that people in Africa are already subclinically infected with arteriviruses. Similar to HIV-1 infections that spread undetected for decades prior to virus discovery in the 1980s (Korber et al., 2000; Worobey et al., 2008), human arterivirus infections may already cause unmeasured disease. HIV-1-induced AIDS kills by secondary infections and hence was etiologically difficult to pinpoint.

Simian arterivirus infection may result in a similar scenario, in subclinical infections, or in acute epidemics of hemorrhagic fever.

Development of serology tests and other measures for human surveillance will be required to understand and detect human exposure to these viruses. These tools are needed in African regions where endemically infected nonhuman primates live.

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