Lessons from HIVs
HIVs are the most studied viruses in history and the best model to understand the interplay between virus and host antiviral defence. Tracing the origins of HIVs would provide a framework for us to understand cross-species transmission and pathogenicity of SARS-CoV-2. The comparison of SARS-CoV-2 and HIVs would reveal a common theme and the requirements for their successful species jumping. In particular, lessons learnt from HIVs are highly relevant and instructive to SARS-CoV-2 for the following reasons. First, both HIVs and SARS-CoV-2 are of zoonotic origin. Second, infection of their reservoir hosts with parental viruses of HIVs and SARS-CoV-2 results in no or mild symptoms. However, when they infect humans, much more severe symptoms are developed. Third, the similarities and differences between HIV-1 and HIV-2 resemble those between SARS-CoV and SARS-CoV-2. Finally, both HIVs and SARS-CoV-2 are plausibly derived from discrete cross-species transmission events from animals to humans. Thus, we will briefly review our current understanding of the origins of HIVs and how host anti-HIV defence has shaped the emergence of the pandemic HIV strains.
There is persuasive evidence that HIVs are derived from multiple cross-species transmissions of simian immunodeficiency viruses (SIVs) that naturally infect African non-human primates. The pandemic HIV-1 strain of group M originated from a single transmission event from a chimpanzee that harbours SIVcpz near Cameroon in Central Africa. Multiple other transmission events of SIVs from chimpanzees to humans were also detected, but their resulting HIV-1 viruses in groups N, O and P spread in humans only to a limited extent [44]. Group O was found in a few tens of thousands of people in West-Central Africa. Groups N and P were identified in 13 and 2 individuals, respectively. Likewise, appreciable spreading of HIV-2 within humans is seen only with groups A and B resulting from two cross-species transmissions of SIVsmm from sooty mangabeys in West Africa [44]. All other groups (C–H) were found only in single individuals. Thus, both HIV-1 and HIV-2 originated from one or two primate-to-human transmission events. The other transmission events were unproductive, representing incidents in which secondary and tertiary spreading was very limited.
SIVs are non-pathogenic in their natural hosts, but their transmission to a new host, such as humans for HIV-1 and HIV-2 as well as macaques for SIVmac, enable them to become highly pathogenic. HIV-1 and HIV-2 share 40–60% nucleotide sequence homology. The transmission rate of HIV-2 is lower because the viral load is generally lower in infected individuals. The natural history of HIV-2 infection is quite different from that of HIV-1. Although clinical symptoms of acquired immunodeficiency syndrome (AIDS) caused by HIV-1 and HIV-2 are indistinguishable, most people infected with HIV-2 do not progress to AIDS. One strong predictor of disease progression that distinguishes pathogenic HIV infection and non-pathogenic SIV infection is the activation of host antiviral defence including a prominent stimulation of T cells in the former but not the latter. Another possibility is that the natural hosts of SIVs might be the survivors of ancient SIV pandemics. One prediction is that HIVs and humans will eventually adapt to each other just like SIVs and their natural hosts. In this regard, AIDS might be considered an accident in which HIVs fail to adapt to humans or humans fail to adapt to HIVs. In support of this view, species-specific features in host restriction factors, such as TRIM5α and tetherin, can prevent SIV infection of humans. On the other hand, adaptive mutations and accessory genes such as Vpu, Nef, and Vif in HIVs have been found to counteract host restriction factors, which constitute the antiviral defence, in a host-specific manner. For example, a five-codon deletion in the cytoplasmic domain of human restriction factor tetherin results in the prevention of its interaction with SIVcpz Nef in humans [45]. On the side of the virus, some HIV-1 strains use their Vpu protein to degrade tetherin [45].
The origins of another pair of human retroviruses named human T lymphotropic viruses 1 and 2 (HTLV-1 and HTLV-2) are also very similar and relevant to HCoVs [46]. HTLV-1 and HTLV-2 share ∼70% nucleotide sequence homology. Whereas HTLV-1 causes a highly lethal disease named adult T-cell leukaemia and another immune-mediated disorder of the spinal cord, the related virus HTLV-2 is largely non-pathogenic and non-oncogenic. Both viruses have counterparts in non-human primates and so are HTLV-3 and HTLV-4 newly discovered in Cameroonian hunters of non-human primates [47]. At least four cross-species transmission events of HTLVs have been identified, each of which involves a different species of primates. The spreading of HTLV-3 and HTLV-4 is very limited in humans, but HTLV-1 and HTLV-2 have infected millions of people. The infection of T lymphocytes with HTLV-2 provides a good example of asymptomatic infection in humans.
HIVs and SARS-CoVs bear many similarities in terms of cross-species transmission. It is difficult to predict how the ongoing outbreak of SARS-CoV-2 might develop in the coming weeks and months. Unprecedented measures have now been taken to isolate the sources of SARS-CoV-2 infection, to block human-to-human transmission and to protect the susceptible individuals. It remains to be seen whether and to what extent secondary and tertiary spreading will be weakened and prevented by the control measures. Apparently, the intrafamily transmission of SARS-CoV-2 has not been stopped in the epicentre of Wuhan after 23 January 2020, when the city was locked down and human gathering was prohibited. It also remains to be determined what percentage of the general population in Wuhan have been or are being infected by SARS-CoV-2. These are important research questions that should be set as priority. However, as seen in HIV-1, HIV-2, HTLV-3, and HTLV-4, not every animal-to-human transmission event gives rise to a virus that is highly and sustainably transmissible within humans. The transmission of SARS-CoV-2 might be stopped due to the intrinsic characteristics of the virus, the action of human restriction factors, and human intervention measures. Another possibility is that SARS-CoV-2 becomes highly transmissible within humans just like the other four community-acquired HCoVs. Some estimates of the transmission rate expressed as reproductive number (R0) of SARS-CoV-2 fall within the range of 3–4, which is higher than that of SARS-CoV (Table 1). If that can be sustained, SARS-CoV-2 will be well adapted to humans ultimately. It will be fortunate if it also becomes less pathogenic, resembling 229E, OC43, HKU1, and NL63. Plausibly, when they initially crossed species barriers to infect humans decades or centuries ago, 229E, OC43, HKU1, and NL63 might have also caused pandemics in which humans were suffering from more severe respiratory diseases. As mentioned above, one such pandemic recorded at the end of nineteenth century has now been linked to the jumping of OC43 from cattle to humans [26].
Table 1. Comparison between SARS-CoV and SARS-CoV-2.
  SARS-CoV SARS-CoV-2
Virus origin Horseshoe bats as evolutionary reservoir host
Civets as intermediate amplifying host
Unknown reservoir host(s)? Rhinolophus affinis bats as evolutionary reservoir host
Unknown intermediate amplifying host(s)?
Unknown reservoir host(s)?
Entry receptor ACE2 as entry receptor
Both human ACE2 and civet ACE2 capable of supporting SARS-CoV entry
Mouse ACE2 less efficient in supporting entry of SARS-CoV when compared with human ACE2 ACE2 from humans, Rhinolophus sinicus bats, civets and swine as entry receptor [35]
Mouse ACE2 unable to serve as entry receptor [35]
Human-to-human transmission route Droplets in most cases
Close contact with contaminated fomites
Faecal–oral
Aerosols uncommon but possible under special circumstances Droplets in most cases
Close contact with contaminated fomites
Faecal–oral
Aerosols uncommon but possible under special circumstances
Higher attack rate within family clusters
Superspreading events Superspreading events detected in Hong Kong and Beijing [8] Superspreading events suspected as in the Diamond Princess cruise ship.
Clinical presentations Lower respiratory infection
ICU care required in ∼30% patients
ARDS in ∼20% patients
Gastrointestinal and CNS infection Lower respiratory infection [36]
ICU care required in 5–10% patients
ARDS in 5% patients [36]
Gastrointestinal infection
Asymptotic carriers [51]
Case fatality 9.6% worldwide 3.4% worldwide as of 24 February 2020 (4.0% in Hubei Province, China, and 0.84% elsewhere)
Transmissibility R0 = 2a R0 = 3–4b
Interferon antagonists nsp1, nsp3, nsp16, ORF3b, ORF6, M and N proteins nsp1, nsp3, nsp16, ORF3b, ORF6, M and N proteins?
Inflammasome activators ORF3a, ORF8b, and E proteins ORF3a, ORF8, and E proteins?
aR0 is <1 for tertiary and quaternary spreading as well as in the later phase.
bIt remains to be seen as to whether R0 will substantially reduce in tertiary and quaternary spreading as well as in the later phase.