have been associated with several diseases [32
] and the KIR3DS1
gene has engendered particular attention in HIV disease pathogenesis (). Although most genetic association studies agree that KIR3DS1
, an allele that has a phenotypic frequency of ~39% in European Americans and 12% in African Americans, is probably protective against HIV, different conclusions regarding the requirement for the putative ligand Bw4–80I have emerged.
Multiple effects of KIR3DL1/S1 on HIV-1 infection and disease progression
in combination with HLA-B Bw4
was associated with slow progression to AIDS in a group of ~1000 HIV seroconverters, and neither Bw4
had any effect on disease progression [56
]. There was a weak protective effect of this compound genotype on viral load, and a rather strong protective effect against opportunistic infections in 1184 individuals, which included the seroconverters used in the previous study and 109 additional seroprevalent individuals [57
Smaller studies arrived at somewhat different conclusions. In a study of a group of 191 individuals [58
], the opposite effect was observed: KIR3DS1
considered by itself and the compound genotype of KIR3DS1
was associated with rapid progression to AIDS, and this was statistically significant for KIR3DS1
. However, KIR3DS1
appeared to be protective in terms of CD4 decline relative to having KIR3DS1
alone, although this effect was not significant. Because only 34 individuals were positive for both KIR3DS1
, it is difficult to know whether the opposite effect of this compound genotype on CD4 decline and progression to AIDS could be at least partially due to power issues. Rather than a KIR3DS1
effect, this study [58
] revealed a detrimental effect of KIR2DL2
on CD4 T cell decline and progression to AIDS.
A study of 255 individuals indicated that KIR3DS1
independently associates with higher CD4 T cell counts, but does not have an effect on viral load levels [59
]. On the other hand, Bw4
independently associated with lower viral loads, but had no effect on CD4 counts. The group with KIR3DS1
had lower viral loads and higher CD4 T cell counts, but not significantly in either case. The authors concluded that both KIR3DS1
are protective, but not in a synergistic manner.
As the genetic association studies did not reach entirely concordant results, it is of interest to consider functional studies on the interaction between KIR3DS1, HLA-B and HIV. Mouse data point to the possibility that activating NK receptors can detect a combination of MHC class I and a virus (i.e. ‘altered self’) [30
]. Given the remarkable degree of convergent evolution between mouse Ly49
and human KIR
in terms of function, it is not unreasonable to consider specific allotypes of HLA class I as ligands for activating KIR upon viral infection or some other cellular lesion.
The protective effect of KIR3DS1 + Bw4
was substantiated with functional data measuring inhibition of HIV replication in an autologous effector-target cell assay amongst a group of 36 individuals with various KIR-HLA
], the first study to address the functional significance of a KIR-HLA
genetic association. In this study, KIR3DS1 positive NK cells inhibited HIV replication in Bw4–80I positive T cells to a significantly greater extent relative to the three other putatively ‘null’ situations: KIR3DS1 positive NK cells in response to Bw4–80I negative T cells, KIR3DS1 negative NK cells in response to Bw4–80I positive T cells, or KIR3DS1 negative NK cells in response to Bw4–80I negative T cells. Based on the functional and genetic data, a model was proposed in which KIR3DS1 on NK cells interacts with Bw4–80I on HIV infected target cells, conferring a measurable level of control over the virus.
More recently, NK cells from HIV infected patients were tested for IFN-γ production and CD107a upregulation, both markers of activation, after stimulation with HLA class I negative targets [60
]. The strongest effects were observed in assays measuring IFN-γ production, where NK cells from KIR3DS1
positive individuals showed greater production of IFN-γ compared to those without KIR3DS1
. This was also the case for the KIR3DS1
positive group compared to those who did not have this compound genotype, and for those with KIR3DS1
compared to those who have KIR3DS1
, but are missing Bw4
]. Statistics measuring strength of the effect of these genotypes were not provided in this study, but the strength of the response to class I deficient targets appeared greatest for the comparison of those with the compound genotype KIR3DS1+ Bw4
versus those without this genotype. Interestingly, KIR3DS1
positive individuals showed a rather strong IFN-γ response compared to those who have KIR3DS1
, but are missing Bw4
. However, statistical power was limited in this comparison because the number of individuals in both groups were small (11 versus 9, respectively) and the difference was not significant. The authors concluded that KIR3DS1
associates with high NK cell functions in a manner that is independent of Bw4
, but an increase in sample numbers in the KIR3DS1+ Bw4
positive versus KIR3DS1
negative comparison groups would help solidify or refute this conclusion. Together, these findings suggest that KIR3DS1 positive NK cells are intrinsically more active, an effect that might depend on HLA-B.
Biological science is rarely straightforward and even small differences in the way two different studies are performed (in terms of either experimental or analytical methodology) can affect the outcome, and therefore the conclusions of a study. However, one possibility is that KIR3DS1 binds certain Bw4 alleles, perhaps after modulation by HIV infection.