Persistent SARS-CoV-2 infection and increasing viral variants in children and young adults with impaired humoral immunity

Truong, Tu T.; Ryutov, Alex; Pandey, Utsav; R, Yee; Goldberg, Leonard S.; Bhojwani, Deepa; Aguayo-Hiraldo, Paibel; Ba, Pinsky; Pekosz, Andrew; Shen, Lishuang; Sd, Boyd; Wirz, Oliver F.; Röltgen, Katharina; Bootwalla, Moiz S.; Dt, Maglinte; Ostrow, Dejerianne; Ruble, David; Han, Jing; Ja, Biegel; M, Li; Huang, ChunHong; Mk, Sahoo; Ps, Pannaraj; O’Gorman, Maurice R.G.; Ar, Judkins; Gai, Xiaowu; J, Dien Bard

doi:10.1101/2021.02.27.21252099

Cited by 38 publications

(38 citation statements)

References 27 publications

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“…There have been relatively few published descriptions of persistent SARS-CoV-2 infection, the majority associated with B cell immunodeficiency (7,10,27,(41)(42)(43)(44). Conversion to PCR negativity and dramatic symptomatic improvement was achieved only after administration of casirivimab and imdevimab.…”

Section: Discussionmentioning

confidence: 99%

Chronic SARS-CoV-2 infection and viral evolution in a hypogammaglobulinaemic individual

Williamson

Hamilton

Hutchings

et al. 2021

Preprint

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There is widespread interest in the capacity for SARS-CoV-2 evolution in the face of selective pressures from host immunity, either naturally acquired post-exposure or from vaccine acquired immunity. Allied to this is the potential for long perm persistent infections within immune compromised individuals to allow a broader range of viral evolution in the face of sub-optimal immune driven selective pressure. Here we report on an immunocompromised individual who is hypogammaglobulinaemic and was persistently infected with SARS-CoV-2 for over 290 days, the longest persistent infection recorded in the literature to date. During this time, nine samples of viral nucleic acid were obtained and analysed by next-generation sequencing. Initially only a single mutation (L179I) was detected in the spike protein relative to the prototypic SARS-CoV-2 Wuhan-Hu-1 isolate, with no further changes identified at day 58. However, by day 155 the spike protein had acquired a further four amino acid changes, namely S255F, S477N, H655Y and D1620A and a two amino acid deletion (ΔH69/ΔV70). Infectious virus was cultured from a nasopharyngeal sample taken on day 155 and next-generation sequencing confirmed that the mutations in the virus mirrored those identified by sequencing of the corresponding swab sample. The isolated virus was susceptible to remdesivir in vitro, however a 17-day course of remdesivir started on day 213 had no effect on the viral RT-PCR cycle threshold (Ct) value. On day 265 the patient was treated with the combination of casirivimab and imdevimab. The patient experienced progressive resolution of all symptoms over the next 8 weeks and by day 311 the virus was no longer detectable by RT-PCR. The ΔH69/ΔV70 deletion in the N-terminus of the spike protein which arose in our patient is also present in the B.1.1.7 variant of concern and has been associated with viral escape mutagenesis after treatment of another immunocompromised patient with convalescent plasma. Our data confirms the significance of this deletion in immunocompromised patients but illustrates it can arise independently of passive antibody transfer, suggesting the deletion may be an enabling mutation that compensates for distant changes in the spike protein that arise under selective pressure.

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Section: Discussionmentioning

confidence: 99%

Chronic SARS-CoV-2 infection and viral evolution in a hypogammaglobulinaemic individual

Williamson

Hamilton

Hutchings

et al. 2021

Preprint

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“…These mutations are located in three distinct hotspots -N-terminal domain (NTD), receptorbinding domain (RBD), and Furin cleavage site (Figure 2A). Mutation E484K was present in the highest number of unrelated lineages [11, Table 1], followed by L452R [10], P681H [9], Y144Δ [8], HV69-70Δ [6], Q677H [6] and N501Y [6]; these mutations thus display the strongest convergent evolution. The overall load of convergent mutations in the S-protein was quantified (lineage parallelism score, Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…The mutations that do not follow this trend are L452R, F490S, T478K, and S494P; we thus speculate that their benefits for viral fitness are likely connected with the host immune system. The immunocompromised patients, treated or non-treated with convalescent plasma or neutralizing antibodies, have been regarded crystal balls for prediction of viral evolution (7,8), showing the emergence of N501Y, S494P, Q493K, Y489H, E484K, T478K and N440D (9, 10) variants during infection. Surprisingly, only mutations E484K and N501Y arose convergently among patients, and their emergence was restricted to a low number of patients.…”

Section: Discussionmentioning

confidence: 99%

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SARS-CoV-2 convergent evolution as a guide to explore adaptive advantage

Zahradník

Nunvář

Schreiber

2021

Preprint

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Much can be learned from 1.2 million sequences of SARS-CoV-2 generated during the last 15 months. Out of the overwhelming number of mutations sampled so far, only few rose to prominence in the viral population. Many of these emerged recently and independently in multiple lineages. Such a textbook example of convergent evolution at the molecular level is not only curiosity but a guide to uncover the basis for adaptive advantage behind these events. Focusing on the extent of the convergent evolution in the spike (S) protein, our report confirms that the most concerning SARS-CoV-2 lineages carry the heaviest burden of convergent S-protein mutations, suggesting their fundamental adaptive advantage. The great majority (21/25) of S-protein sites under convergent evolution tightly cluster in three functional domains; N-terminal domain, receptor-binding domain, and Furin cleavage site. We further show that among the S-protein receptor-binding motif mutations, ACE2 affinity-improving substitutions are favored. While the probed mutation space in the S protein covered all amino-acids reachable by single nucleotide changes, substitutions requiring two nucleotide changes or epistatic mutations of multiple-residues have only recently started to emerge. Unfortunately, despite their convergent emergence and physical association, most of these adaptive mutations and their combinations remain understudied. We aim to promote research of current variants which are currently understudied but may become important in the future.

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“…Moreover, some studies have shown that selective pressure from therapeutic mAbs or convalescent serum could induce E484K or E484Q mutations 26,27 . These results indicate the importance of E484 in the viral epitope.…”

Section: Discussionmentioning

confidence: 99%

Comparison of 10 emerging SARS-CoV-2 Variants: infectivity, animal tropism, and antibody neutralization

Zhang

Cui

et al. 2021

Preprint

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Ten emerging SARS-CoV-2 variants—B.1.1.298, B.1.1.7, B.1.351, P.1, P.2, B.1.429, B.1.525, B.1.526-1, B.1.526-2, B.1.1.318—and seven corresponding single amino acid mutations in the receptor-binding domain were examined using SARS-CoV-2 pseudovirus. The results indicate that the current SARS-CoV-2 variants do not increase infectivity among humans. The K417N/T, N501Y, or E484K-carrying variants exhibited increased abilities to infect to mouse ACE2-overexpressing cells. The activities of Furin, TMPRSS2, and cathepsin L were increased against most of the variants. RBD amino acid mutations comprising K417T/N, L452R, Y453F, S477N, E484K, and N501Y caused significant immune escape from 11 of 13 monoclonal antibodies. However, the resistance to neutralization by convalescent serum or vaccines was mainly caused by the E484K mutation, while the neutralization of E484K-carrying variants was decreased by 1.1–6.2-fold. The convalescent serum from B.1.1.7- and B.1.351-infected patients neutralized the variants themselves better than other SARS-CoV-2 variants.

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Persistent SARS-CoV-2 infection and increasing viral variants in children and young adults with impaired humoral immunity

Cited by 38 publications

References 27 publications

Chronic SARS-CoV-2 infection and viral evolution in a hypogammaglobulinaemic individual

Chronic SARS-CoV-2 infection and viral evolution in a hypogammaglobulinaemic individual

SARS-CoV-2 convergent evolution as a guide to explore adaptive advantage

Comparison of 10 emerging SARS-CoV-2 Variants: infectivity, animal tropism, and antibody neutralization

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