ABSTRACT
Introduction Circulating levels, and the ex vivo production, of the chemokines
CCL3, CCL4, CCL5, CXCL8 and CXCL12 (known to play an important role in
the pathogenesis of either human immunodeficiency virus type 1 (HIV-1) or
tuberculosis (TB)) were examined in the context of both single infections with
HIV-1 or Mycobacterium tuberculosis (Mtb) and coinfection with both
organisms. We hypothesised that CCL3L1 gene copy number (known to affect
CCL3 production, associated with susceptibility to and disease progression of
HIV-1) would be associated with mother-to-child transmission (MTCT) of HIV-1,
and that the IL8-251T→A single nucleotide polymorphism (SNP) (associated
with enhanced CXCL8 production and susceptibility to TB in African Americans)
would be highly represented in the South African Black population.
Methods Samples used included (i) plasma, DNA samples and cell culture
supernatants from control, HIV-1, TB and HIV-1/TB groups, (ii) DNA samples
from mothers and their infants (grouped as HIV-1 exposed-uninfected, infected
in utero, or infected intrapartum), and (iii) DNA samples from a populationbased
study cohort. Chemokines were quantified by enzyme-linked
immunosorbent assay (ELISA), CCL3L1 gene copy numbers were determined
by real-time polymerase chain reaction (PCR), and a real-time PCR method
was developed for identification of the IL8-251T→A SNP. DNA sequencing was
used for confirmation.
Results We found reduced ex vivo chemokine production in response to
phytohaemagglutinin (PHA) together with increased plasma levels of
chemokines in HIV-1 and TB patients. In contrast to that seen in Caucasians
(median CCL3L1 copy number of 2), in Black individuals (median CCL3L1 copy
number of 5) circulating levels of CCL3 did not correlate with CCL3L1 gene
copy number; in addition, a high proportion of Black individuals were found to
have CCL3L1 copy numbers below their population-specific median. Using
MTCT as a model for studying HIV-1 transmission, infants who became infected
with HIV-1 had significantly reduced CCL3L1 gene copy numbers. IL8-251A
allele frequencies were found to be 0.41 for Caucasian groups, and 0.85 for
Black groups; due to study limitations, the possible association of IL8-251T→A
with TB susceptibility could not be addressed.
Discussion The increased plasma levels of chemokines seen in HIV-1 and TB,
likely due to chronic immune activation in vivo, may result in T cell anergy which
in turn might be the cause of reduced PHA-stimulated ex vivo chemokine
production. Our results suggest that Black South Africans may be at particularly
high risk for acquiring HIV-1 (at least with respect to CCL3L1 gene copy
number), and further imply the presence of other genetic polymorphisms which
may influence plasma CCL3 levels. In addition, the high IL8-251A allele
frequency (if indeed associated with TB in South African populations) in Black
individuals suggests a greater risk for infection with Mtb. It will be important, in
larger studies, to gain a more in-depth understanding of the relationships
between host genotype and chemokine production phenotype, and to relate
these measures to infection outcomes.
Conclusions Together, these results highlight the importance of gaining an
understanding of the effects of host genotype on the development of innate and
acquired immunity to HIV-1 and TB, which will be key in the design of efficient
therapies and prevention strategies.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/6909 |
| Date | 29 April 2009 |
| Creators | Donninger, Samantha Louise |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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