SARS-CoV-2 infection in immunosuppression evolves sub-lineages which independently accumulate neutralization escape mutations

Gila Lustig; Yashica Ganga; Hylton E Rodel; Houriiyah Tegally; Afrah Khairallah; Laurelle Jackson; Sandile Cele; Khadija Khan; Zesuliwe Jule; Kajal Reedoy; Farina Karim; Mallory Bernstein; Thumbi Ndung'u; Mahomed-Yunus S Moosa; Derseree Archary; Tulio de Oliveira; Richard Lessells; Richard A Neher; Salim S Abdool Karim; Alex Sigal

doi:10.1093/ve/vead075

SARS-CoV-2 infection in immunosuppression evolves sub-lineages which independently accumulate neutralization escape mutations

Virus Evol. 2023 Dec 28;10(1):vead075. doi: 10.1093/ve/vead075. eCollection 2024.

Authors

Gila Lustig¹, Yashica Ganga², Hylton E Rodel^{2

3}, Houriiyah Tegally^{4

5}, Afrah Khairallah², Laurelle Jackson², Sandile Cele^{2

6}, Khadija Khan^{2

6}, Zesuliwe Jule², Kajal Reedoy², Farina Karim^{2

6}, Mallory Bernstein², Thumbi Ndung'u^{2

3

6

7

8}, Mahomed-Yunus S Moosa⁹, Derseree Archary¹, Tulio de Oliveira^{4

5

10}, Richard Lessells⁴, Richard A Neher^{11

12}, Salim S Abdool Karim^{1

13}, Alex Sigal^{1

2

6}

Affiliations

¹ Centre for the AIDS Programme of Research in South Africa, 719 Umbilo Road, Durban 4001, South Africa.
² Africa Health Research Institute, 719 Umbilo Road, Durban 4001, South Africa.
³ Division of Infection and Immunity, University College London, UCL Cruciform Building Gower Street, London WC1E 6BT, UK.
⁴ KwaZulu-Natal Research Innovation and Sequencing Platform, 719 Umbilo Road, Durban 4001, South Africa.
⁵ Centre for Epidemic Response and Innovation, School of Data Science and Computational Thinking, Stellenbosch University, Francie Van Zijl Drive, Cape Town 7505, South Africa.
⁶ School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, 719 Umbilo Road, Durban 4001, South Africa.
⁷ HIV Pathogenesis Programme, University of KwaZulu-Natal, 719 Umbilo Road, Durban 4001, South Africa.
⁸ Ragon Institute of MGH, MIT and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA.
⁹ Department of Infectious Diseases, Nelson R. Mandela School of Clinical Medicine, University of KwaZulu-Natal, 719 Umbilo Road, Durban 4001, South Africa.
¹⁰ Department of Global Health, University of Washington, 3980 15th Avenue NE, Seattle, WA 98105, USA.
¹¹ SIB Swiss Institute of Bioinformatics, Quartier Sorge - Bâtiment Amphipôle, Lausanne 1015, Switzerland.
¹² Biozentrum, University of Basel, Spitalstrasse 41 4056, Basel, Switzerland.
¹³ Department of Epidemiology, Mailman School of Public Health, Columbia University, 722 West 168th Street, New York, NY 10032, United States.

Abstract

One mechanism of variant formation may be evolution during long-term infection in immunosuppressed people. To understand the viral phenotypes evolved during such infection, we tested SARS-CoV-2 viruses evolved from an ancestral B.1 lineage infection lasting over 190 days post-diagnosis in an advanced HIV disease immunosuppressed individual. Sequence and phylogenetic analysis showed two evolving sub-lineages, with the second sub-lineage replacing the first sub-lineage in a seeming evolutionary sweep. Each sub-lineage independently evolved escape from neutralizing antibodies. The most evolved virus for the first sub-lineage (isolated day 34) and the second sub-lineage (isolated day 190) showed similar escape from ancestral SARS-CoV-2 and Delta-variant infection elicited neutralizing immunity despite having no spike mutations in common relative to the B.1 lineage. The day 190 isolate also evolved higher cell-cell fusion and faster viral replication and caused more cell death relative to virus isolated soon after diagnosis, though cell death was similar to day 34 first sub-lineage virus. These data show that SARS-CoV-2 strains in prolonged infection in a single individual can follow independent evolutionary trajectories which lead to neutralization escape and other changes in viral properties.

Keywords: SARS-CoV-2 evolution; advanced HIV disease; immunosuppression; prolonged infection; variants of concern.