Abstract
BackgroundAiming 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.MethodsA 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.ResultsReverse 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.ConclusionsThe 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.
Highlights
Knowledge of early events in infection is essential for understanding HIV-1 pathogenesis
Correlates of protection in HIV-1 infection are still elusive, it is widely believed that the breadth of immune response plays an important role in disease outcome, and is likely to be associated with the breadth of viral mutational pathways
To address the question of when in vivo Gag mutations occur, we focused on examining the time of appearance, dominance, completeness, and loss of different types of viral mutations in Gag soon after seroconversion over the first year of HIV-1 subtype C infection in a cohort of 42 subjects with estimated time of seroconversion
Summary
Knowledge of early events in infection is essential for understanding HIV-1 pathogenesis. In natural HIV-1 infection, viral mutational pathways that are not directly related to ART are still poorly understood. This is because in most studies the time of infection is rarely available, which makes synchronizing viral mutations extremely difficult. When the time of infection or seroconversion can be reliably identified [1,2,3,4], the time course of these mutations relative to infection or seroconversion can be established. Surprisingly little attention has been devoted to the timing of viral mutations in the natural course of HIV infection. It is likely that knowledge of timing constraints on viral mutations could shape preventive and therapeutic strategies by identifying optimal times of intervention. 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
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