Higher HIV-1 evolutionary rate is associated with cytotoxic T lymphocyte escape mutations in infants
Jamirah Nazziwa 1 2, Sophie M Andrews 3, Mimi M Hou 3, Christian A W Bruhn 1, Miguel A Garcia-Knight 3 4, Jennifer Slyker 5 6, Sarah Hill 7, Barbara Lohman Payne 8 9, Dorothy Moringas 8, Philippe Lemey 10, Grace John-Stewart 5 6 9 11 12, Sarah L Rowland-Jones # 3, Joakim Esbjörnsson # 1 2 3
Affiliations
- 1Department of Translational Medicine, Lund University, Lund, Sweden.
- 2Lund University Virus Centre, Lund University, Lund, Sweden.
- 3Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
- 4Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, USA.
- 5Department of Global Health, University of Washington, Seattle, Washington, USA.
- 6Department of Epidemiology, University of Washington, Seattle, Washington, USA.
- 7Department of Pathobiology and Population Sciences, Royal Veterinary College, London, United Kingdom.
- 8Department of Paediatrics and Child Health, University of Nairobi, Nairobi, Kenya.
- 9Department of Medicine, University of Washington, Seattle, Washington, USA.
- 10Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.
- 11Department of Pediatrics, University of Washington, Seattle, Washington, USA.
- 12Global Center for Integrated Health of Women, Adolescents and Children (Global WACh), University of Washington, Seattle, Washington, USA.
#Contributed equally.
- PMID: 38814066
- DOI: 10.1128/jvi.00072-24
Abstract
Escape from cytotoxic T lymphocyte (CTL) responses toward HIV-1 Gag and Nef has been associated with reduced control of HIV-1 replication in adults. However, less is known about CTL-driven immune selection in infants as longitudinal studies of infants are limited. Here, 1,210 gag and 1,264 nef sequences longitudinally collected within 15 months after birth from 14 HIV-1 perinatally infected infants and their mothers were analyzed. The number of transmitted founder (T/F) viruses and associations between virus evolution, selection, CTL escape, and disease progression were determined. The analyses indicated that a paraphyletic-monophyletic relationship between the mother-infant sequences was common (80%), and that the HIV-1 infection was established by a single T/F virus in 10 of the 12 analyzed infants (83%). Furthermore, most HIV-1 CTL escape mutations among infants were transmitted from the mothers and did not revert during the first year of infection. Still, immune-driven selection was observed at approximately 3 months after HIV-1 infection in infants. Moreover, virus populations with CTL escape mutations in gag evolved faster than those without, independently of disease progression rate. These findings expand the current knowledge of HIV-1 transmission, evolution, and CTL escape in infant HIV-1 infection and are relevant for the development of immune-directed interventions in infants.IMPORTANCEDespite increased coverage in antiretroviral therapy for the prevention of perinatal transmission, paediatric HIV-1 infection remains a significant public health concern, especially in areas of high HIV-1 prevalence. Understanding HIV-1 transmission and the subsequent virus adaptation from the mother to the infant's host environment, as well as the viral factors that affect disease outcome, is important for the development of early immune-directed interventions for infants. This study advances our understanding of vertical HIV-1 transmission, and how infant immune selection pressure is shaping the intra-host evolutionary dynamics of HIV-1.
Keywords: CTL responses; HIV-1; disease progression; infant; intra-host evolution; vertical transmission.