Abstract
Pregnant women have abundant natural killer (NK) cells in their placenta, and NK cell function is regulated by polymorphisms of killer cell immunoglobulin-like receptors (KIRs). Previous studies report different roles of NK cells in the immune responses to placental malaria (PM) and human immunodeficiency virus (HIV-1) infections. Given these references, the aim of this study was to determine the association between KIR gene content polymorphism and PM infection in pregnant women of known HIV-1 status. Sixteen genes in the KIR family were analyzed in 688 pregnant Kenyan women. Gene content polymorphisms were assessed in relation to PM in HIV-1 negative and HIV-1 positive women, respectively. Results showed that in HIV-1 negative women, the presence of the individual genes KIR2DL1 and KIR2DL3 increased the odds of having PM, and the KIR2DL2/KIR2DL2 homozygotes were associated with protection from PM. However, the reverse relationship was observed in HIV-1 positive women, where the presence of individual KIR2DL3 was associated with protection from PM, and KIR2DL2/KIR2DL2 homozygotes increased the odds for susceptibility to PM. Further analysis of the HIV-1 positive women stratified by CD4 counts showed that this reverse association between KIR genes and PM remained only in the individuals with high CD4 cell counts but not in those with low CD4 cell counts. Collectively, these results suggest that inhibitory KIR2DL2 and KIR2DL3, which are alleles of the same locus, play a role in the inverse effects on PM and PM/HIV co-infection and the effect of KIR genes on PM in HIV positive women is dependent on high CD4 cell counts. In addition, analysis of linkage disequilibrium (LD) of the PM relevant KIR genes showed strong LD in women without PM regardless of their HIV status while LD was broken in those with PM, indicating possible selection pressure by malaria infection on the KIR genes.
Highlights
In sub-Saharan Africa, it is estimated that 32 million pregnant women are at risk for Plasmodium falciparum infection annually [1]
We provide the first evidence that 1) the killer cell immunoglobulin-like receptors (KIRs) gene content polymorphism is associated with placental malaria (PM) infection, 2) this association is affected by the HIV status of the pregnant women, and 3) the effect of KIR gene content polymorphism on PM infection in the HIV positive women is dependent on high CD4 cell counts
We identified associations between KIR2DL1, KIR2DL2, and KIR2DL3 genes and PM infection
Summary
In sub-Saharan Africa, it is estimated that 32 million pregnant women are at risk for Plasmodium falciparum infection annually [1]. Parity-dependent malarial immunity is acquired over consecutive pregnancies protecting multigravid women against the adverse effect of pregnancy-associated malaria, and as a consequence, in high transmission areas susceptibility to malaria decreases with increasing gravidity, whereas in areas of low endemicity, this trend is not as evident. HIV-1 infection in women of reproductive age is another major public health problem and often coexists with malaria in pregnant women in sub-Saharan Africa [6]. HIV complicates the adverse consequences of placental malaria (PM) by increasing risk of infection, parasite densities and severity of the disease [7,8] and by impairing the response to anti-malarial therapy [9]. Six studies addressed whether PM enhanced MTCT and all were conducted prior to the widespread introduction of antiretrovirals (ARVs) with conflicting conclusions [11,12,13,14,15,16], showing increased MTCT in two studies in Uganda [11,15], no effect in two other studies at the Kenya Coast [13,14], and a significant protective effect in Mozambique and western Kenya [12,16]
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