Year: 2009
Type: dissertation
Study design: Observational Study
Abstract: ABSTRACT \nIntroduction Circulating levels, and the ex vivo production, of the chemokines \nCCL3, CCL4, CCL5, CXCL8 and CXCL12 (known to play an important role in \nthe pathogenesis of either human immunodeficiency virus type 1 (HIV-1) or \ntuberculosis (TB)) were examined in the context of both single infections with \nHIV-1 or Mycobacterium tuberculosis (Mtb) and coinfection with both \norganisms. We hypothesised that CCL3L1 gene copy number (known to affect \nCCL3 production, associated with susceptibility to and disease progression of \nHIV-1) would be associated with mother-to-child transmission (MTCT) of HIV-1, \nand that the IL8-251T→A single nucleotide polymorphism (SNP) (associated \nwith enhanced CXCL8 production and susceptibility to TB in African Americans) \nwould be highly represented in the South African Black population. \nMethods Samples used included (i) plasma, DNA samples and cell culture \nsupernatants from control, HIV-1, TB and HIV-1/TB groups, (ii) DNA samples \nfrom mothers and their infants (grouped as HIV-1 exposed-uninfected, infected \nin utero, or infected intrapartum), and (iii) DNA samples from a populationbased \nstudy cohort. Chemokines were quantified by enzyme-linked \nimmunosorbent assay (ELISA), CCL3L1 gene copy numbers were determined \nby real-time polymerase chain reaction (PCR), and a real-time PCR method \nwas developed for identification of the IL8-251T→A SNP. DNA sequencing was \nused for confirmation. \nResults We found reduced ex vivo chemokine production in response to \nphytohaemagglutinin (PHA) together with increased plasma levels of \nchemokines in HIV-1 and TB patients. In contrast to that seen in Caucasians \n(median CCL3L1 copy number of 2), in Black individuals (median CCL3L1 copy \nnumber of 5) circulating levels of CCL3 did not correlate with CCL3L1 gene \ncopy number; in addition, a high proportion of Black individuals were found to \nhave CCL3L1 copy numbers below their population-specific median. Using \nMTCT as a model for studying HIV-1 transmission, infants who became infected \nwith HIV-1 had significantly reduced CCL3L1 gene copy numbers. IL8-251A \nallele frequencies were found to be 0.41 for Caucasian groups, and 0.85 for \nBlack groups; due to study limitations, the possible association of IL8-251T→A \nwith TB susceptibility could not be addressed. \nDiscussion The increased plasma levels of chemokines seen in HIV-1 and TB, \nlikely due to chronic immune activation in vivo, may result in T cell anergy which \nin turn might be the cause of reduced PHA-stimulated ex vivo chemokine \nproduction. Our results suggest that Black South Africans may be at particularly \nhigh risk for acquiring HIV-1 (at least with respect to CCL3L1 gene copy \nnumber), and further imply the presence of other genetic polymorphisms which \nmay influence plasma CCL3 levels. In addition, the high IL8-251A allele \nfrequency (if indeed associated with TB in South African populations) in Black \nindividuals suggests a greater risk for infection with Mtb. It will be important, in \nlarger studies, to gain a more in-depth understanding of the relationships \nbetween host genotype and chemokine production phenotype, and to relate \nthese measures to infection outcomes. \nConclusions Together, these results highlight the importance of gaining an \nunderstanding of the effects of host genotype on the development of innate and \nacquired immunity to HIV-1 and TB, which will be key in the design of efficient \ntherapies and prevention strategies.
Author: Samantha L. Donninger
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2151904555