Abstract
BackgroundThe role of copy number variation of the CCL3L1 gene, encoding MIP1α, in contributing to the host variation in susceptibility and response to HIV infection is controversial. Here we analyse a sub-Saharan African cohort from Tanzania and Ethiopia, two countries with a high prevalence of HIV-1 and a high co-morbidity of HIV with tuberculosis.MethodsWe use a form of quantitative PCR called the paralogue ratio test to determine CCL3L1 gene copy number in 1134 individuals and validate our copy number typing using array comparative genomic hybridisation and fiber-FISH.ResultsWe find no significant association of CCL3L1 gene copy number with HIV load in antiretroviral-naïve patients prior to initiation of combination highly active anti-retroviral therapy. However, we find a significant association of low CCL3L1 gene copy number with improved immune reconstitution following initiation of highly active anti-retroviral therapy (p = 0.012), replicating a previous study.ConclusionsOur work supports a role for CCL3L1 copy number in immune reconstitution following antiretroviral therapy in HIV, and suggests that the MIP1α -CCR5 axis might be targeted to aid immune reconstitution.
Highlights
The role of copy number variation of the CCL3L1 gene, encoding MIP1α, in contributing to the host variation in susceptibility and response to HIV infection is controversial
This is shown by the fosmid probe labelled red, which maps to the CCL3L1 repeat and has been used previously to estimate copy number in humans [35]
Of the 14 CCL3L1 repeats directly visualised in these three trios, 11 have a repeat structure that includes a fosmid probe, labelled in green, which covers a region between the CCL4 gene and the TBC1D3 and CCL3L1 genes
Summary
The role of copy number variation of the CCL3L1 gene, encoding MIP1α, in contributing to the host variation in susceptibility and response to HIV infection is controversial. African countries currently have the highest disease burden of HIV, with 9.2% prevalence in Addis Ababa in Ethiopia and over 10% in Dar-es-Salaam in Tanzania, yet almost all genetic studies have focused on cohorts from Western countries [2]. The genetic architecture of HIV susceptibility in Africans is likely to be different to Europeans, yet genome-wide association studies of host susceptibility to HIV have not yielded any significant results [3]. These studies miss regions that show copy number variation, structurally complex. CNV of the killer cell immunoglobulin receptor genes has been shown to affect host control of HIV infection, as determined by the viral load (VL) at setpoint [8], and we have recently shown association of β-defensin CNV both with HIV viral load at initiation of highly-active anti-retroviral therapy (HAART) and with consequent immune reconstitution [9]
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