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

Date Published: November 5, 2009

Publisher: Public Library of Science

Author(s): 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, Linqi Zhang.

Abstract: 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.

Partial Text: Knowledge of early events in infection is essential for understanding HIV-1 pathogenesis. Although 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. 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. In contrast, when the time of infection or seroconversion can be reliably identified [1]–[4], the time course of these mutations relative to infection or seroconversion can be established. To date, 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.

Timing patterns of viral mutational pathways in the natural course of HIV-1 infection are not well understood, and denote a knowledge gap in HIV research. In this study, we addressed timing of in vivo Gag mutations during primary HIV-1 subtype C infection in a prospective cohort of 8 acutely and 34 recently infected individuals from Botswana. Despite a significant heterogeneity between subjects in the time of appearance, dominance, and completeness of amino acid substitutions in Gag during the early phase of HIV-1 subtype C infection, we found that the in vivo reverse mutations to the wild type in Gag occurred significantly earlier than escape mutations from the wild type.



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