Timing constraints of in vivo Gag mutations during primary HIV-1 subtype C infection

Vladimir Novitsky, Rui Wang, Lauren Margolin, Jeannie Baca, Lemme Kebaabetswe, Raabya Rossenkhan, Caitlin Bonney, Michaela Herzig, David Nkwe, Sikhulile Moyo, Rosemary Musonda, Elias Woldegabriel, Erik van Widenfelt, Joseph Makhema, Stephen Lagakos, M. Essex

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Abstract

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.

Original languageEnglish
Article numbere7727
JournalPLoS One
Volume4
Issue number11
DOIs
Publication statusPublished - Nov 5 2009

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Human immunodeficiency virus 1
HIV-1
Hazards
seroconversion
mutation
Mutation
Infection
infection
Amplification
Genes
dominance (genetics)
Seroconversion

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Novitsky, V., Wang, R., Margolin, L., Baca, J., Kebaabetswe, L., Rossenkhan, R., ... Essex, M. (2009). Timing constraints of in vivo Gag mutations during primary HIV-1 subtype C infection. PLoS One, 4(11), [e7727]. https://doi.org/10.1371/journal.pone.0007727
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. In: PLoS One. 2009 ; Vol. 4, No. 11.
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abstract = "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.",
author = "Vladimir Novitsky and Rui Wang and Lauren Margolin and Jeannie Baca and Lemme Kebaabetswe and Raabya Rossenkhan and Caitlin Bonney and Michaela Herzig and David Nkwe and Sikhulile Moyo and Rosemary Musonda and Elias Woldegabriel and {van Widenfelt}, Erik and Joseph Makhema and Stephen Lagakos and M. Essex",
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Novitsky, V, Wang, R, Margolin, L, Baca, J, Kebaabetswe, L, Rossenkhan, R, Bonney, C, Herzig, M, Nkwe, D, Moyo, S, Musonda, R, Woldegabriel, E, van Widenfelt, E, Makhema, J, Lagakos, S & Essex, M 2009, 'Timing constraints of in vivo Gag mutations during primary HIV-1 subtype C infection', PLoS One, vol. 4, no. 11, e7727. https://doi.org/10.1371/journal.pone.0007727

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.

In: PLoS One, Vol. 4, No. 11, e7727, 05.11.2009.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Timing constraints of in vivo Gag mutations during primary HIV-1 subtype C infection

AU - Novitsky, Vladimir

AU - Wang, Rui

AU - Margolin, Lauren

AU - Baca, Jeannie

AU - Kebaabetswe, Lemme

AU - Rossenkhan, Raabya

AU - Bonney, Caitlin

AU - Herzig, Michaela

AU - Nkwe, David

AU - Moyo, Sikhulile

AU - Musonda, Rosemary

AU - Woldegabriel, Elias

AU - van Widenfelt, Erik

AU - Makhema, Joseph

AU - Lagakos, Stephen

AU - Essex, M.

PY - 2009/11/5

Y1 - 2009/11/5

N2 - 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.

AB - 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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