# HIV Evolution Defines Virus-Host/Drug Interactions In Viremic and Aviremic People

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $658,797

## Abstract

Viral gene sequences represent a rich and valuable source of information about biological
processes. Advances in next generation sequencing (NGS) technology over the past decade
now provide the opportunity to probe viral population diversity and evolution in unprecedented
ways. We developed specialized sequencing strategies to overcome several serious limitations
of conventional NGS in analyzing viral populations, including greatly reducing the mis-
incorporation and recombination introduced by the preceding PCR step, reducing the errors of
the sequencing platform, and revealing sampling depth of the initial viral genomes/templates
that are actually represented in the final data set. In this application we will use state-of-the-art
NGS to address long-standing issues in HIV-1 population analysis in the context of viral
evolution in the absence of therapy, the role of minor variants in predicting failed therapy, and
whether the latent reservoir on therapy is replicating. In addition, we will link our sequence data
to state-of-the-art evolutionary analysis, and confirm key aspects of our inferences with
measures of changing viral phenotypes and host environment. In Aim 1, we will analyze
longitudinal plasma samples from 27 HIV-infected women (from the WIHS cohort) starting with
high CD4+ T cell counts until they progress to CD4+ T cell counts of less than 100 cells/µL. We
will perform multiplexed NGS sequencing to obtain near full length HIV-1 genome sequences.
We predict that X4 variants in viral populations first emerge at low abundance and that we will
be able to detect them much earlier than previously observed and follow their evolution. In
addition, we will investigate longitudinal viral diversity changes in all sequenced regions to
assess population dynamics and link these changes to markers of inflammation, CNS damage,
CTL response, and the breadth and potency of neutralizing antibodies. In Aim 2, we will apply
multiplexed NGS sequencing as a screening tool for minor drug resistance variants that predict
therapy failure. We hypothesize that the potential for drug resistance mutations to mediate
escape can occur from minor variants, too minor to be reliably detected with the methods that
have been used to date. We will analyze samples from four cohorts (Malawi and China) to
determine how often minor variants are missed by using Sanger sequencing. We will then link
resistance mutations leading to therapy failure with their pretherapy abundance in a case-
control design. In Aim 3, we will use near full length genome sequencing of reservoir virus
(either outgrowth or rebound) in 13 participants who were infected with a single variant and
started therapy early. Potential evolution on therapy will include a focus on extant CTL
responses. In this way we will provide a critical test of sequence evolution as a signature of viral
replication during years of successful suppressive therapy. With this application we are
examining questions that are cent...

## Key facts

- **NIH application ID:** 10180893
- **Project number:** 5R01AI140970-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Ronald I Swanstrom
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $658,797
- **Award type:** 5
- **Project period:** 2018-06-25 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180893

## Citation

> US National Institutes of Health, RePORTER application 10180893, HIV Evolution Defines Virus-Host/Drug Interactions In Viremic and Aviremic People (5R01AI140970-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10180893. Licensed CC0.

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