Chemokine production in HIV-1 infection and pulmonary tuberculosis

Donninger, Samantha Louise
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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.
HIV-1, pulmonary tuberculosis, chemokine production