# Impact of Non - B HIV - 1 Subtype on second line Protease Inhibitor Regimens in Africa (INSPIRE)

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $715,198

## Abstract

Abstract of research
The finding that most patients with virologic failure (HIV-1 RNA >=1,000cp/mL) on second-line PI-
containing regimens lack PI-resistance mutations in the protease (PR) gene is one of the main
enigmas of antiretroviral drug resistance research. We hypothesized that env and gag sequences
from these patients contain compensatory mutations, specifically in the Env, that confer PI
resistance. A role of the gp41 CT in PI resistance may be linked to the role of virus maturation,
triggered by PR, in activating Env fusion activity. In recent years, increasing numbers of clinical
reports have observed failure of DTG-containing therapy in the absence of integrase (IN)
mutations, suggesting that mutations outside IN may confer resistance in these patients. Our
studies demonstrated the first instance of de novo selection of Env mutations that confer
resistance to Dolutegravir (DTG) in vitro (unpublished data). We attribute this phenotype to the
ability of the Env mutants to mediate highly efficient cell-to-cell transmission, resulting in an
increase in the multiplicity of infection. In addition, up to 20-, 6- and 24-fold reduction in
susceptibility to ATV, DRV and LPV, respectively, was observed in absence of PR mutations
among HIV-1 CRF_02AG and subtype G infected patients. These findings have broad
implications for our understanding of Env and Gag functions and the evolution of HIV-1 drug
resistance. Our goal is to identify factors that predict virological failure (VF) on ATV/r or LPV/r as
patients with VF on a PI-containing regimens have suboptimal future treatment and may be at an
increased risk for developing integrase resistance inhibitor on a third-line regimen. A collaborative
team involving investigators led by the Institute of Human Virology Nigeria will exploit robust
longitudinal cohorts (Cameroon, Nigeria and Uganda) of patients on 2L regimens, coupled to well-
characterized and archived clinical specimens that underpin a rigorous nested case-control study
design.
To test these interlocking hypotheses, we propose to: (i) use our newly developed HIV-xGen next
generation sequencing method to extend understanding of viral evolution and HIV drug resistance
across the viral genome and to determine whether there is effect modification by non-B HIV-1
subtypes, (ii) characterize recombinant viruses carrying mutations identified in Aim 1, using
established phenotypic assays to determine their effect on drug susceptibility and site-directed
mutagenesis, and lastly (iii) determine differences in replicative fitness on drug susceptibility with
use of a yeast recombination-based cloning system. Our plans to study these patients and their
viruses (subtype A, C, D, G, and CRF02_AG, CRF43_02G, HIV-1 O and HIV-1 N) provides a
unique opportunity to determine the phenotypic and clinical significance of genotypic changes in
HIV-1 gag, gag-pol and env genes. All in all, this proposal will permit exciting epidemiological,
clinical, and public heal...

## Key facts

- **NIH application ID:** 10150764
- **Project number:** 7R01AI147331-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Manhattan E Charurat
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $715,198
- **Award type:** 7
- **Project period:** 2020-04-27 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10150764

## Citation

> US National Institutes of Health, RePORTER application 10150764, Impact of Non - B HIV - 1 Subtype on second line Protease Inhibitor Regimens in Africa (INSPIRE) (7R01AI147331-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10150764. Licensed CC0.

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