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Timing Constraints of In Vivo Gag Mutations during Primary HIV-1 Subtype C Infection

BACKGROUND: Aiming to answer the broad question “When does mutation occur?” this study examined the time of appearance, dominance, and completeness of in vivo Gag mutations in primary HIV-1 subtype C infection. METHODS: A primary HIV-1C infection cohort comprised of 8 acutely and 34 recently infecte...

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Autores principales: Novitsky, Vladimir, Wang, Rui, Margolin, Lauren, Baca, Jeannie, Kebaabetswe, Lemme, Rossenkhan, Raabya, Bonney, Caitlin, Herzig, Michaela, Nkwe, David, Moyo, Sikhulile, Musonda, Rosemary, Woldegabriel, Elias, van Widenfelt, Erik, Makhema, Joseph, Lagakos, Stephen, Essex, M.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768328/
https://www.ncbi.nlm.nih.gov/pubmed/19890401
http://dx.doi.org/10.1371/journal.pone.0007727
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author Novitsky, Vladimir
Wang, Rui
Margolin, Lauren
Baca, Jeannie
Kebaabetswe, Lemme
Rossenkhan, Raabya
Bonney, Caitlin
Herzig, Michaela
Nkwe, David
Moyo, Sikhulile
Musonda, Rosemary
Woldegabriel, Elias
van Widenfelt, Erik
Makhema, Joseph
Lagakos, Stephen
Essex, M.
author_facet Novitsky, Vladimir
Wang, Rui
Margolin, Lauren
Baca, Jeannie
Kebaabetswe, Lemme
Rossenkhan, Raabya
Bonney, Caitlin
Herzig, Michaela
Nkwe, David
Moyo, Sikhulile
Musonda, Rosemary
Woldegabriel, Elias
van Widenfelt, Erik
Makhema, Joseph
Lagakos, Stephen
Essex, M.
author_sort Novitsky, Vladimir
collection PubMed
description BACKGROUND: Aiming to answer the broad question “When does mutation occur?” this study examined the time of appearance, dominance, and completeness of in vivo Gag mutations in primary HIV-1 subtype C infection. METHODS: A primary HIV-1C infection cohort comprised of 8 acutely and 34 recently infected subjects were followed frequently up to 500 days post-seroconversion (p/s). Gag mutations were analyzed by employing single-genome amplification and direct sequencing. Gag mutations were determined in relation to the estimated time of seroconversion. Time of appearance, dominance, and completeness was compared for different types of in vivo Gag mutations. RESULTS: Reverse mutations to the wild type appeared at a median (IQR) of 62 (44;139) days p/s, while escape mutations from the wild type appeared at 234 (169;326) days p/s (p<0.001). Within the subset of mutations that became dominant, reverse and escape mutations appeared at 54 (30;78) days p/s and 104 (47;198) days p/s, respectively (p<0.001). Among the mutations that reached completeness, reverse and escape mutations appeared at 54 (30;78) days p/s and 90 (44;196) days p/s, respectively (p = 0.006). Time of dominance for reverse mutations to and escape mutations from the wild type was 58 (44;105) days p/s and 219 (90;326) days p/s, respectively (p<0.001). Time of completeness for reverse and escape mutations was 152 (100;176) days p/s and 243 (101;370) days p/s, respectively (p = 0.001). Fitting a Cox proportional hazards model with frailties confirmed a significantly earlier time of appearance (hazard ratio (HR): 2.6; 95% CI: 2.3–3.0), dominance (4.8 (3.4–6.8)), and completeness (3.6 (2.3–5.5)) of reverse mutations to the wild type Gag than escape mutations from the wild type. Some complex mutational pathways in Gag included sequential series of reversions and escapes. CONCLUSIONS: The study identified the timing of different types of in vivo Gag mutations in primary HIV-1 subtype C infection in relation to the estimated time of seroconversion. Overall, the in vivo reverse mutations to the wild type occurred significantly earlier than escape mutations from the wild type. This shorter time to incidence of reverse mutations remained in the subsets of in vivo Gag mutations that reached dominance or completeness.
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spelling pubmed-27683282009-11-05 Timing Constraints of In Vivo Gag Mutations during Primary HIV-1 Subtype C Infection Novitsky, Vladimir Wang, Rui Margolin, Lauren Baca, Jeannie Kebaabetswe, Lemme Rossenkhan, Raabya Bonney, Caitlin Herzig, Michaela Nkwe, David Moyo, Sikhulile Musonda, Rosemary Woldegabriel, Elias van Widenfelt, Erik Makhema, Joseph Lagakos, Stephen Essex, M. PLoS One Research Article BACKGROUND: Aiming to answer the broad question “When does mutation occur?” this study examined the time of appearance, dominance, and completeness of in vivo Gag mutations in primary HIV-1 subtype C infection. METHODS: A primary HIV-1C infection cohort comprised of 8 acutely and 34 recently infected subjects were followed frequently up to 500 days post-seroconversion (p/s). Gag mutations were analyzed by employing single-genome amplification and direct sequencing. Gag mutations were determined in relation to the estimated time of seroconversion. Time of appearance, dominance, and completeness was compared for different types of in vivo Gag mutations. RESULTS: Reverse mutations to the wild type appeared at a median (IQR) of 62 (44;139) days p/s, while escape mutations from the wild type appeared at 234 (169;326) days p/s (p<0.001). Within the subset of mutations that became dominant, reverse and escape mutations appeared at 54 (30;78) days p/s and 104 (47;198) days p/s, respectively (p<0.001). Among the mutations that reached completeness, reverse and escape mutations appeared at 54 (30;78) days p/s and 90 (44;196) days p/s, respectively (p = 0.006). Time of dominance for reverse mutations to and escape mutations from the wild type was 58 (44;105) days p/s and 219 (90;326) days p/s, respectively (p<0.001). Time of completeness for reverse and escape mutations was 152 (100;176) days p/s and 243 (101;370) days p/s, respectively (p = 0.001). Fitting a Cox proportional hazards model with frailties confirmed a significantly earlier time of appearance (hazard ratio (HR): 2.6; 95% CI: 2.3–3.0), dominance (4.8 (3.4–6.8)), and completeness (3.6 (2.3–5.5)) of reverse mutations to the wild type Gag than escape mutations from the wild type. Some complex mutational pathways in Gag included sequential series of reversions and escapes. CONCLUSIONS: The study identified the timing of different types of in vivo Gag mutations in primary HIV-1 subtype C infection in relation to the estimated time of seroconversion. Overall, the in vivo reverse mutations to the wild type occurred significantly earlier than escape mutations from the wild type. This shorter time to incidence of reverse mutations remained in the subsets of in vivo Gag mutations that reached dominance or completeness. Public Library of Science 2009-11-05 /pmc/articles/PMC2768328/ /pubmed/19890401 http://dx.doi.org/10.1371/journal.pone.0007727 Text en Novitsky et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Novitsky, Vladimir
Wang, Rui
Margolin, Lauren
Baca, Jeannie
Kebaabetswe, Lemme
Rossenkhan, Raabya
Bonney, Caitlin
Herzig, Michaela
Nkwe, David
Moyo, Sikhulile
Musonda, Rosemary
Woldegabriel, Elias
van Widenfelt, Erik
Makhema, Joseph
Lagakos, Stephen
Essex, M.
Timing Constraints of In Vivo Gag Mutations during Primary HIV-1 Subtype C Infection
title Timing Constraints of In Vivo Gag Mutations during Primary HIV-1 Subtype C Infection
title_full Timing Constraints of In Vivo Gag Mutations during Primary HIV-1 Subtype C Infection
title_fullStr Timing Constraints of In Vivo Gag Mutations during Primary HIV-1 Subtype C Infection
title_full_unstemmed Timing Constraints of In Vivo Gag Mutations during Primary HIV-1 Subtype C Infection
title_short Timing Constraints of In Vivo Gag Mutations during Primary HIV-1 Subtype C Infection
title_sort timing constraints of in vivo gag mutations during primary hiv-1 subtype c infection
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768328/
https://www.ncbi.nlm.nih.gov/pubmed/19890401
http://dx.doi.org/10.1371/journal.pone.0007727
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