Human immunodeficiency virus type 1 (HIV-1) isolates can be differentiated based
on their ability to use particular coreceptors – R5 viruses use CCR5, X4 viruses use
CXCR4 and R5X4 (dual tropic) viruses use both CCR5 and CXCR4. It is widely
reported that HIV-1 subtype C (HIV-1C) has a unique viral coreceptor evolution
pattern in that a complete switch from the predominant CCR5 (R5) to CXCR4 (X4)
phenotype is less common for this subtype compared to other subtypes. However,
dual tropic HIV-1C isolates have occasionally been described. Furthermore, it has
been reported that certain highly active antiretroviral drugs (HAART) may select for
X4 viral variants. Therefore, this thesis study was undertaken to better understand the
functional and genotypic characteristics of dual tropic HIV-1C isolates, and to
characterize drug resistance and coreceptor usage patterns in HAART-naïve versus
HAART-failing HIV-1C infected patients.
Thirty-five functional HIV-1 env clones derived from seven dual tropic HIV-1C
strains were generated and their coreceptor usage characterized in transformed cell
lines. All 35 env clones efficiently infected transformed cells expressing CXCR4.
Twenty of 35 clones (57%) also utilized the CCR5 receptor. No R5-only clones were
detected. Functional coreceptor usage data was correlated to env gene sequence data.
The ability of the HIV-1C env clones to facilitate infection of primary lymphocytes
and monocyte-derived macrophages was next investigated. The majority of clones
characterized as X4 or R5X4 on cell lines used either CXCR4 alone or CXCR4 and
CCR5, respectively, in primary cells. A few viruses displayed comparable CCR5 and
CXCR4 usage and clones from one virus preferred CCR5 usage in macrophages.
Thus in a few cases coreceptor phenotyping in transformed cell lines does not predict
usage in primary cells. Genetic determinants for coreceptor usage in primary cells
require further investigation.
Finally the patterns of drug resistance mutations were studied and coreceptor usage
among 45 HAART-naïve and 45 HAART-failing HIV-1C infected patients analyzed.
Ninety-five percent of HAART-failing patients had viruses with at least one drug
resistance mutation. Thymidine analog resistance mutations (TAMs) were present in
55% of patients. HAART-failing patients had significantly higher prevalence (59%)
of X4/R5X4-utilizing viruses compared to HAART-naïve patients (30%) (p<0.02)
using the Trofile Co-receptor Tropism Assay while 41% of HAART-failing patients
used CCR5 and 70% of HAART-naïve patients used CCR5. Functional results
correlated with predictive algorithm methods.
This study enhances our understanding of HIV-1 pathogenesis and the results have
important implications for the use of coreceptor antagonists for the clinical
management of HIV-1C infection. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2011.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ukzn/oai:http://researchspace.ukzn.ac.za:10413/9636 |
| Date | January 2010 |
| Creators | Singh, Ashika. |
| Contributors | Ndung'u, Thumbi. |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
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