Co-evolution of antibody lineages and HIV epitopes
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Date
2019
Authors
Mabvakure, Batsirai Macdonald
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Abstract
The HIV envelope glycoprotein (Env) is enormously variable, making it very difficult to
represent this diversity in a vaccine. Exposure of the immune system to the
continuously diversifying viral quasispecies leads to an “arms race” that contributes to
the evolution of the antibody response, and virus escape. Another consequence of this
within-host HIV diversity is that viral populations may differ between compartments,
with phenotypic effects that may impact the sensitivity of viruses to
vaccines/microbicides. The aim of the study is to investigate the role of HIV envelope
diversity in driving development of strain-specific or broadly neutralizing (bNAb)
responses among hosts, and compartmentalization within hosts, using low-cost
computational infrastructure.
We first compared viral diversity among hosts by studying eight HIV-1 infected
participants who developed bNAbs and six donors who did not develop bNAbs over
three years of infection. Defining the viral evolution that contributes to breadth is a
major focus of the field so as to elicit bNAbs through vaccination. Comparison of Envs
from individuals with bNAbs and strain-specific antibodies revealed that gross
evolutionary measures such as Env diversity, evolutionary rates and number of viral
infections are not sufficient to distinguish the two groups. However, bNAb donors had
more positive selection within targeted sites, with some residues shared between
bNAb donors. The positive selection at these common sites increased with the onset
of neutralization breadth. The association of shared, positively selected sites with the
emergence of breadth highlights the importance of diversity at these positions in bNAb
development.
We next investigated the viral properties in different compartments within the same
individual, as this is important for understanding the potential efficacy of HIV-directed
antibodies and microbicides. We compared longitudinal viral Envs between the genital
tract and blood plasma of four women. We found evidence of compartmentalization in
two of the four individuals. In all four individuals there was restricted viral migration
from the genital tract to the systemic blood circulation suggesting a mucosal sieve
effect. However, this restricted viral migration was more pronounced in the two
individuals who had evidence of compartmentalization. We identified several sites in
the Env that differed between viruses in the two compartments, and that arose through
positive selection and/or indels. This resulted in charge distribution differences which
may differentially impact the sensitivity of these viruses to antibody responses.
Overall, these findings show that HIV viruses in the female genital tract may evolve
differently from those in plasma, and develop properties that may potentially impact
the efficacy of vaccines.
These studies relied on high numbers of Env sequences isolated at multiple timepoints,
making these analyses computationally intensive. We thus designed and implemented
a low-cost bioinformatics cluster for analysing large sequencing datasets (including
next generation sequencing). Cluster design included meeting memory requirements,
parallelization and long computational times. In addition to supporting viral studies
described above, we used the cluster to trace an antibody lineage isolated from an
HIV-infected donor, CAP228. The antibody lineage, CAP228-16H/19F, exhibited
genetic characteristics similar to the monoclonal antibody, CH58, isolated from the
RV144 human vaccine trial. Our analyses identified the unmutated common ancestor
(UCA) that initiated the CAP228-16H/19F lineage, and showed that this was derived
from a novel allele that encodes an amino acid DDxD motif that was responsible for
binding to the V1V2 epitope on Env. This is in contrast to previous studies which
suggested that binding was limited to an unusual ED motif that occurs rarely in the
immunoglobulin repertoire. The identification of the DDxD motif thus demonstrated that
there is a greater potential for eliciting these antibody responses through vaccination
as the alleles encoding this motif are common in the population. Overall, this approach
to high-performance computing is important as an alternative for data processing
challenges faced in low-income communities that are unable to afford advanced
computational infrastructure.
In conclusion, firstly, these analyses show the importance of diversity at specific amino
acid residues in driving bNAb development, which may have valuable implications for
vaccination design. Secondly, the study addresses the important subject of whether
HIV compartmentalization occurs or not between the female genital tract and plasma,
with findings that may impact on vaccine design. Lastly, we demonstrate the
development and application of cheaper data processing infrastructure, an approach
which may help researchers from low-income settings to overcome challenges in
performing computationally intensive analyses.
Description
thesis submitted in fulfilment of the requirements for the degree of
Doctor of philosophy (PhD)
University of the Witwatersrand, Johannesburg
March 2019
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Citation
Mabvakure, Batsirai Macdonald, Co-evolution of antibody lineages and HIV epitopes, University of the Witwatersrand, Johannesburg, <http://hdl.handle.net/10539/29746>