>Magister Scientiae - MSc / Determination of CXCR4-usage patterns is essential in establishing suitability
of CCR5 antagonist prescription in HIV-1 infected individuals to
prevent treatment failure. Previous studies have suggested a switch to
CXCR4-usage to be far less common in subtype C, yet recent studies
have reported between 30 - 50% CXCR4-usage in this subtype. However,
CXCR4-usage in subtype C is poorly characterised. Furthermore,
the reliability of available genotypic algorithms is unknown for subtype C
sequences.
In this study, a comparative analysis of the predictive ability of several
subtype B-modeled genotyping algorithms in subtype C tropism determination
was undertaken. A total of 731 HIV-1 subtype C V3 sequences with
phenotypically determined coreceptor tropism were collated from several
sources. Datasets of 349 CCR5, 25 CXCR4 exclusive and 31 R5X4 (Dual)
sequences were submitted to 11 various tropism prediction tools. The best
performing tool was used to determine the tropism of 12,121 subtype C V3
sequences with unknown phenotypes, in order to characterise the prevalence
and method of CXCR4 usage in HIV-1 subtype C.
We determined that geno2pheno with a false positive rate of 5% is the best
approach for predicting CXCR4-usage in subtype C sequences with an
accuracy of 94% (89% sensitivity and 99% specificity). Contrary to what
has been reported for subtype B, the optimal approaches for prediction
of CXCR4-usage in sequence from viruses that use CXCR4 exclusively,
also perform best at predicting CXCR4-use in dual-tropic viral variants.
Furthermore, we find that a switch to CXCR4 usage is seen in subtype C
for well over 20 years and has occurred consistently over time. At 5%, the
frequency of CXCR4-usage in subtype C database records is lower than
previous reports for both subtype C and B.
The Geno2pheno coreceptor tool may be used as a reliable genotypic predictor
in clinical settings to establish the viability of CCR5-antagonist
therapies using drugs such as Maraviroc and provides a rapid and cost
effective alternative to phenotypic testing in resource limited areas. A
switch to CXCR4-usage in subtype C is constant but lower when compared
to subtype B, a finding which may have broad implications for the
design of intervention and treatment strategies for HIV-1 subtype C.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:uwc/oai:etd.uwc.ac.za:11394/4041 |
| Date | January 2013 |
| Creators | Crous, Saleema |
| Contributors | Travers, Simon A |
| Publisher | University of the Western Cape |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Rights | University of the Western Cape |
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