Mutational pathways in early HIV infection: novel guide to immunologic analyses

Harvard School Of Public Health, Boston MA

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Abstract

DESCRIPTION (provided by applicant): The lack of understanding of the correlates of protection may lie, at least partially, in the fact that historically virus-host interactions have not been studied interactively, but rather by focusing on a single side of the equation. The hypothesis of this study is built on the assumptions that viral mutational pathways in natural HIV-1 infection are restricted by the viral in vivo evolutionary space, and that viral evolutionary space within a given host is confined by a dynamic balance between immune responses and viral fitness. We hypothesize that comprehensive assessment of viral mutational pathways in the early phase of HIV-1 infection may help in formulating specific immunologic questions leading to thorough interactive analysis of virus-specific immune responses, and is likely to result in better understanding of HIV pathogenesis. Applying a novel approach of direct mapping of Gag mutations along the time line of HIV-1 infection, patterns of viral dynamics will be assessed with a particular focus on timing and relationships between different types of viral mutations, and will be translated to a series of specific immunologic hypotheses revealing the mechanisms of virus-host interactions. Aim 1: To identify and characterize HIV-1C Gag mutational pathways. To map time of appearance, dominance, and completeness (or transiency/loss) of viral mutations in HIV-1C Gag by utilizing prospective sample sets with estimated time of seroconversion and applying single-genome amplification/sequencing and ultra-deep sequencing (in a subset). Aim 2: To design a series of immunologically relevant hypotheses focusing on the dynamic interactions between immune responses and viral mutational pathways. The specific immunologic questions will be addressed based on actual mutational pathways, and therefore, will improve existing methods of assessing virus-specific T cell responses in primary HIV infection, and will help to explore correlates and mechanisms of immune protection in future studies. The proposed study will reveal early evolutionary dynamics of host-virus interactions, and will likely enable better immunogen design. PUBLIC HEALTH RELEVANCE: The lack of understanding of the correlates of protection may lie, at least partially, in the fact that historically virus-host interactions have not been studied interactively, but rather by focusing on a single side of the equation. The study will apply a novel approach of direct mapping of Gag mutations along the time line of HIV-1 infection, and will asses patterns of viral dynamics with a particular focus on timing and relationships between different types of viral mutations. Results will be translated to a series of specific immunologic hypotheses revealing the mechanisms of virus-host interactions.