Consensus Sequences for <i>Gag</i> and <i>Pol</i> Introduced into HIV-1 Clade B Laboratory Strains Differentially Influence the Impact of Point Mutations Associated with Immune Escape and with Drug Resistance on Viral Replicative Capacity
Viral evasion from effective human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses and from antiretroviral therapy through viral sequence variation is frequently accompanied by a loss in viral fitness. The impact of sequence variations on replication capacity in vitro was mostly...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-06-01
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| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/17/6/842 |
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| Summary: | Viral evasion from effective human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses and from antiretroviral therapy through viral sequence variation is frequently accompanied by a loss in viral fitness. The impact of sequence variations on replication capacity in vitro was mostly studied by introducing single mutations into a specific clonal strain such as NL4-3. How the specific viral backbone itself impacts replicative fitness remains elusive. To test for a potential effect of the viral backbone, we constructed HIV-1 clade B clones with consensus sequences for <i>gag</i> and/or <i>pol</i> and evaluated the infectivity of viral variants harboring well-defined cytotoxic T-lymphocyte (CTL) escape mutations or drug resistance mutations within this backbone or the clonal NL4-3 strain. Viral variants with consensus sequences were replication-competent in vitro, although at lower rates than the NL4-3 virus. Introduction of the dominant CTL escape mutation R<sub>264</sub>K into the newly constructed viruses or into NL4-3 led to a dramatic reduction in infection rates. In contrast to the NL4-3 backbone, the combination of R<sub>264</sub>K with its compensatory mutation S<sub>173</sub>A on the consensus backbone led to higher infection rates as compared to the same virus in the absence of R<sub>264</sub>K and S<sub>173</sub>A. Furthermore, 2 out of 10 drug resistance mutations in <i>pol</i> led to opposing effects, with an increase in infection rates on the consensus <i>gag/pol</i> backbone and a reduction on NL4-3. Therefore, the effect of the respective viral backbone on infectivity observed in vitro might constitute an additional factor to explain differential kinetics of mutational evasion from immune and pharmaceutical pressure. |
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| ISSN: | 1999-4915 |