Advisory Committee Chair
Christina Ochsenbauer
Advisory Committee Members
Anju Bansal
Christina Ochsenbauer
John Kappes
Steffanie Sabbaj
Document Type
Thesis
Date of Award
1-1-2025
Degree Name by School
Master of Science (MS) Heersink School of Medicine
Abstract
HIV-1 infects target cells through two primary mechanisms: By attachment, binding and fusion of cell-free (CF) virions to target cells, and through cell-to-cell (CC) transmission of virions, e.g. via virological synapses. Induction of potent bnAbs through vaccination remains a key goal for HIV prevention. Given that in cell culture models CC dependent spread is more resistant to inhibition by bnAbs than CF infection, the CC mode of infection likely presents challenges for inhibiting HIV-1 infection in vivo. It is important to understand the mechanisms by which HIV-1 evades bnAbs in the context of CC spread. Our lab pioneered a novel CC neutralization (CC NAb) assay to quantify inhibition of CC infection by bnAbs. We tested the hypothesis that (i) the efficiency with which HIV Env glycoproteins (Envs) mediate CC spread correlates with their evasion from bnAb neutralization, and (ii) that differences in the CC spread efficiencies of viruses map to amino acid sequence determinants in the Env. The efficiency of HIV-1 CC spread can be described as C-C replicative capacity (ccRC). We quantified ccRC in a novel co-culture system, using CD4 T cells and replication competent HIV-1. We determined the ccRC values for 25 Env strains for which CC NAb assay neutralization data were previously determined against 10 different bnAbs. We then performed a correlation analysis to investigate the relationship between these metrics. We also examined amino acid sequence alignment of the CH0505 longitudinal Env variants with differential ccRC. We performed mutagenesis to swap domains with the most significant sequence discrepancies from CH0505.wk100 into CH0505.wk78, a variant that showed noticeably low CC spread efficiency. We then calculated the ccRC of these mutants. Distinct differences in ccRC were noted amongst Env variants. However, this did not correlate with bnAb neutralization sensitivity in the CC NAb assay, indicating escape from bnAb during CC spread may be influenced by variables other than ccRC. Upon evaluating the ccRC of the domain swapped Envs, our results indicate no gain in function in CC spread efficiency. Additional mutagenesis and structural modeling is necessary to inform which domains in Env may affect spread efficiency.
Recommended Citation
Shah, Yash Jatin, "Examining Replicative Capacity Of Hiv-1 Cell-To-Cell Spread And Correlates With Antibody Neutralization And Molecular Determinants In Env Glycoprotein" (2025). All ETDs from UAB. 6887.
https://digitalcommons.library.uab.edu/etd-collection/6887
Comments
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