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Pathogenesis and Immunity

Mother-to-Child HIV Transmission Bottleneck Selects for Consensus Virus with Lower Gag-Protease-Driven Replication Capacity

Vanessa L. Naidoo, Jaclyn K. Mann, Christie Noble, Emily Adland, Jonathan M. Carlson, Jake Thomas, Chanson J. Brumme, Christina F. Thobakgale-Tshabalala, Zabrina L. Brumme, Mark A. Brockman, Philip J. R. Goulder, Thumbi Ndung'u
Guido Silvestri, Editor
Vanessa L. Naidoo
aHIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
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Jaclyn K. Mann
aHIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
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Christie Noble
bDepartment of Paediatrics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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Emily Adland
bDepartment of Paediatrics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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Jonathan M. Carlson
cMicrosoft Research, Redmond, California, USA
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Jake Thomas
bDepartment of Paediatrics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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Chanson J. Brumme
dBritish Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
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Christina F. Thobakgale-Tshabalala
aHIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
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Zabrina L. Brumme
dBritish Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
eSimon Fraser University, Burnaby, Canada
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Mark A. Brockman
dBritish Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
eSimon Fraser University, Burnaby, Canada
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Philip J. R. Goulder
aHIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
bDepartment of Paediatrics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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Thumbi Ndung'u
aHIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
fAfrica Health Research Institute, Durban, South Africa
gRagon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA
hMax Planck Institute for Infection Biology, Berlin, Germany
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Guido Silvestri
Emory University
Roles: Editor
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DOI: 10.1128/JVI.00518-17
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ABSTRACT

In the large majority of cases, HIV infection is established by a single variant, and understanding the characteristics of successfully transmitted variants is relevant to prevention strategies. Few studies have investigated the viral determinants of mother-to-child transmission. To determine the impact of Gag-protease-driven viral replication capacity on mother-to-child transmission, the replication capacities of 148 recombinant viruses encoding plasma-derived Gag-protease from 53 nontransmitter mothers, 48 transmitter mothers, and 47 infected infants were assayed in an HIV-1-inducible green fluorescent protein reporter cell line. All study participants were infected with HIV-1 subtype C. There was no significant difference in replication capacities between the nontransmitter (n = 53) and transmitter (n = 44) mothers (P = 0.48). Infant-derived Gag-protease NL4-3 recombinant viruses (n = 41) were found to have a significantly lower Gag-protease-driven replication capacity than that of viruses derived from the mothers (P < 0.0001 by a paired t test). High percent similarities to consensus subtype C Gag, p17, p24, and protease sequences were also found in the infants (n = 28) in comparison to their mothers (P = 0.07, P = 0.002, P = 0.03, and P = 0.02, respectively, as determined by a paired t test). These data suggest that of the viral quasispecies found in mothers, the HIV mother-to-child transmission bottleneck favors the transmission of consensus-like viruses with lower viral replication capacities.

IMPORTANCE Understanding the characteristics of successfully transmitted HIV variants has important implications for preventative interventions. Little is known about the viral determinants of HIV mother-to-child transmission (MTCT). We addressed the role of viral replication capacity driven by Gag, a major structural protein that is a significant determinant of overall viral replicative ability and an important target of the host immune response, in the MTCT bottleneck. This study advances our understanding of the genetic bottleneck in MTCT by revealing that viruses transmitted to infants have a lower replicative ability as well as a higher similarity to the population consensus (in this case HIV subtype C) than those of their mothers. Furthermore, the observation that “consensus-like” virus sequences correspond to lower in vitro replication abilities yet appear to be preferentially transmitted suggests that viral characteristics favoring transmission are decoupled from those that enhance replicative capacity.

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Mother-to-Child HIV Transmission Bottleneck Selects for Consensus Virus with Lower Gag-Protease-Driven Replication Capacity
Vanessa L. Naidoo, Jaclyn K. Mann, Christie Noble, Emily Adland, Jonathan M. Carlson, Jake Thomas, Chanson J. Brumme, Christina F. Thobakgale-Tshabalala, Zabrina L. Brumme, Mark A. Brockman, Philip J. R. Goulder, Thumbi Ndung'u
Journal of Virology Aug 2017, 91 (17) e00518-17; DOI: 10.1128/JVI.00518-17

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Mother-to-Child HIV Transmission Bottleneck Selects for Consensus Virus with Lower Gag-Protease-Driven Replication Capacity
Vanessa L. Naidoo, Jaclyn K. Mann, Christie Noble, Emily Adland, Jonathan M. Carlson, Jake Thomas, Chanson J. Brumme, Christina F. Thobakgale-Tshabalala, Zabrina L. Brumme, Mark A. Brockman, Philip J. R. Goulder, Thumbi Ndung'u
Journal of Virology Aug 2017, 91 (17) e00518-17; DOI: 10.1128/JVI.00518-17
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KEYWORDS

HIV Infections
HIV-1
Infectious Disease Transmission, Vertical
virus replication
gag Gene Products, Human Immunodeficiency Virus
human immunodeficiency virus
mother-to-child transmission
transmission bottleneck
viral replication capacity

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