Hughson, Alexandra
(2024)
The effects of clinical HIV-1 mutations on lenacapavir sensitivity and host protein binding to capsid.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
The capsid of human immunodeficiency virus type 1 (HIV-1) encloses two copies of the viral RNA genome and disassembles after cell entry in a highly regulated process called capsid uncoating. HIV-1 capsid uncoating is tightly linked to the process of reverse transcription, in which the viral reverse transcriptase (RT) converts the single-stranded RNA genome into double-stranded DNA. HIV-1 capsid has a unique structure that is highly ordered and conserved, particularly at sites that interact with necessary host factors for infection like cleavage polyadenylation factor 6 (CPSF6) and cyclophilin A (CypA). The newly FDA-approved antiretroviral drug lenacapavir (LCV) is a first-in-class capsid inhibitor. However, several LCV resistance mutations can develop in vivo and in vitro in the shared binding pocket of the capsid protein (CA) where LCV and CPSF6 bind. We hypothesize that the close relationship between capsid and host protein binding proteins is responsible for the development of clinical HIV-1 mutations that may impact LCV and non-nucleoside reverse transcriptase inhibitor (NNRTI) susceptibility. Computational analysis of full-length subtype B HIV-1 sequences from LCV-naive individuals from 2000-2020 revealed a strong association of LCV resistance CA mutations with several NNRTI resistance RT mutations. Using drug susceptibility assays on HIV-1 molecular clones with individual or combinations of CA and RT mutations with LCV or NNRTIs rilpivirine (RPV) and efavirenz (EFV), we demonstrate that NNRTI resistance RT mutations do not confer additional resistance to LCV. Therefore, reducing the concern of further drug resistance development in LCV-treated patients with virus containing those combinations of mutations. However, a HIV-1 mutant with CA mutations conferring increased CypA binding to capsid had reduced sensitivity to LCV. It is possible that CypA binding to HIV-1 capsid may be variable in people living with HIV and some HIV-1 variants could have natural reduced sensitivity to LCV. Our results contribute to the understanding of how CA and RT mutations contribute to antiretroviral drug resistance and will provide vital information to advise future drug development.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
17 May 2024 |
| Date Type: |
Publication |
| Defense Date: |
11 April 2024 |
| Approval Date: |
17 May 2024 |
| Submission Date: |
23 April 2024 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
62 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
MPH - Master of Public Health |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Lenacapavir, HIV-1, capsid |
| Date Deposited: |
17 May 2024 17:23 |
| Last Modified: |
17 May 2024 17:23 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46233 |
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