Natural killer cells are innate immune cells that control certain microbial infections and tumors. The function of natural killers (NK) is regulated by a balance between the signals transmitted by the activating receptors, which recognize the ligands located on cells infected by the virus or on cancer cells, and the inhibitory receptors specific to the molecules of the major histocompatibility complex [1] . NK cells exhibit a variety of surface receptors that can enhance or decrease their response against the target cell. This includes the killer cell immunoglobulin-like receptors (KIRs), encoded by a region of chromosome 19 called the Leukocyte Receptor Complex (LRC) [2] . They are required for natural killer cell function against virus‐infected cells or tumor cells [3] . The polymorphism of these KIR receptors has been linked to several diseases, including infection, autoimmunity, and cancer [4] . KIR molecules are a family of receptors expressed on the surface of natural killer (NK) cells. They constitute one of the first line defense mechanisms of innate immunity against microorganisms and neoplastic cells [4] [5] . The KIR polymorphism has been studied in several populations around the world [4] - [9] . Genotypes have been described in more than 200 diverse populations worldwide [10] . KIR receptors have been associated with pathologies induced by HPV infection around the world [1] [11] - [13] , but very few studies, to our knowledge, have been carried out on African populations. This study is the first to be carried out in west Africa on KIR genes in relation to HPV infection. Studies in Africa on this gene are very few and generally concern HIV or HBV infections [14] - [18] . Due to their function, KIRs may contribute to the clearance of HPV-infected cells and/or dysplastic cells and some studies confirm the association of KIR genes with cervical cancer in women with HPV infection [3] . However, since KIR controls the activity of NK cells, variation in the KIR gene can determine the course of the infection [13] . It would therefore be interesting to study the KIR genes in relation to HPV infection because this knowledge can be exploited to identify potential immunological biomarkers that can help select patients for suitable therapy [19] .

The objective of this study was to investigate the involvement of the KIR genes in Human Papillomavirus (HPV) infections in women in West Africa. Given the sample size, we combined the results for better understanding. The most prevalent genotypes found were HPV 68 (11.33%), HPV 52 (10.86%), HPV 45 (9.22%), followed by genotypes HPV 66 (8.86%), HPV 56 (8.03%), HPV 31 (7.67%), HPV 35, 51, 58, (7.32%), HPV 59 (7.20%), HPV 39 (5.90%); finally, HPV 18 (5.43%), HPV 16 (2.24%) and HPV 33 (1.30%). The HPV 16 and HPV 18 genotypes are among the lowest prevalence. Similar results were found in previous studies in Burkina Faso [21] - [27] . The high prevalence of high-risk genotypes other than 16 and 18 had been found in cases of precancerous and cancerous lesions in Burkina Faso and Benin [28] [29] . In this study, the prevalence of HR-HPV was 35.94%. These results were higher than those found by Traore et al. in Bobo-Dioulasso which was 25.40% [25] . While recently, Salambanga et al. in 2019 found a high prevalence of HR-HPV of 52.56% in the city of Ouagadougou [30] . This high prevalence can also be explained by the fact that the cohort of women included sex workers where there was a high rate of HPV [20] . Fortunately, not all of these HPV-HR infections systematically progress to cervical cancer because of the human factors that regulate clearance. Knowing that the KIR genes are essential in the regulation of the activation of NK cells, it is therefore interesting to ask whether they would potentially have an influence on the infection due to HPV and on the development of precancerous lesions and even of Cancer, because NK cells are the first line of defense against any viral infection and newly formed tumor cells [31] . Our results found that the frequency of KIR genes seem quite close to those found in the literature. The KIR 3DL1 gene is found in virtually all subjects; this is a gene that seems to be unique to West Africa [18] . Contreras had already encountered it in a population of black Mexicans with a frequency of 100% [32] . This was confirmed by Augusto who showed that the KIR 3DL1 gene has a high frequency in Africans [33] . Denis et al. Also found that the KIR 2DS4 activator KIR gene is overrepresented in the Senegalese population [34] . Next to these genes, which have a high frequency, we notice the KIR 3DS1 gene which is less prevalent in most black African populations, corroborating our results [35] . A study of 492 subjects from Kampala, Uganda, indicating that African populations have lower frequencies of telomeric region B and higher frequencies from centromeric region B compared to European populations. This is also the case in South Africa, were in a study involving 167 blacks, the KIR 2DS1 and 3DS1 genes were infrequent [36] . These different data on the KIR genes comfort us because it shows that our results agree with the mapping that already exists around the world. Black Africa has its peculiarities, as does white Africa [6] [33] [34] [37] . We also found that the KIR 2DL5 gene was less prevalent (P = 0.03) in the HPV 16/18 group than in the group made up of other HR-HPV. Also the KIR genes 2DL3, 2DL4, 2DL5, 3DL2 and the pseudogene 2DP1 were more prevalent among cases than in subjects not infected with HPV. This could indicate possible protection against HPV infection. In a cohort study of 65 women with CIN and 150 controls in northern Sweden, Arnheim et al., found 70 different genotypes and only one genotype A was associated with increased risk of CIN including KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL2, KIR3DL3 and KIR2DS4 (OR 6.7; 95% CI 1.7 - 26.3) and the KIR 2DL5 B gene appears to be related to the disease. And there was no association between the KIR genes and the type of HPV [11] . As for the Brestovac team in Western Australia, it had enrolled 147 CIN patients and 187 controls. CIN 2 and 3 were weakly associated with the absence of KIR 2DL2 AND KIR 2DS2, but this value was insignificant. And no difference was observed between KIR frequencies, CINs and HPV genotypes [13] . Tembhurne found that the number of activating KIR genes was higher in women with cancer, as in our study in infected women. The fact that there are high numbers of activating KIR genes may translate into the possibility of a genetic predisposition to chronic inflammatory disease [3] . This chronic inflammation over the years can lead to cancerous lesions and, with persistent HPV infection, These two previous interesting studies have given us information on the absence and presence of certain KIR genes, but it should be remembered that these are cases of precancerous lesions (CIN 1 and CIN 2), whereas our cases were HPV infectious status, which does not necessarily lead to the CIN stage or even cancer due to viral clearance [11] [13] . In Brazil, 79 women infected with HPV and 150 uninfected took part in a study to see the association between HPV and the genes of the immune response [38] . It was found that the KIR genes are not associated with HPV, although certain pairs of inhibitory KIR ligands are more common in patients, which supports the role of NK in harmful inflammation and chronic carcinogenesis. Our results are also different from those of Song in Korean women. No relationship between KIR genes and HPV-related cervical disease was found but a significant relationship was found between HLA-C alleles as ligands in KIR and HPV-related cervical disease [39] . HLA-C * 0303 was found to confer susceptibility to HPV-related cervical disease, while HLA-C * 01 was found to confer a protective effect against HPV-related cervical disease [39] while Rizzo showed that HLA-C and KIR typing is a marker for the risk of HPV infection and the progression of the lesion [40] . Indeed, as in our study, Rizzo et al. found an increase in the KIR 2DL3 gene in cases compared to controls. But it was in association with HLA-C1 [40] .

This study shows that the HR-HPV genotypes circulating in our regions are not dominated by genotypes 16 and 18 among asymptomatic women. This has implications for vaccine use to prevent infection. It would be interesting to get pharmaceutical companies to develop polyvalent broad-spectrum anti-HPV vaccines taking into account all the HPV-HR genotypes found in studies from the West Africa region. Studies on KIR genes give a first insight into their distribution in this West African population. The inhibitory KIR genes, KIR2DL3, KIR2DL4, KIR2DL5, KIR3DL2 and the pseudogene KIR2DP1 were statistically associated with HPV infection. KIR/HLA studies combined with additional genotyping are needed to investigate the molecular mechanisms by which KIR genes contribute to infection or elimination of HPV.

We thank the “International Center for Genetic Engineering and Biotechnology (ICGEB)” for funding this research work through the project: “Implication of the host genetic factor in Human Papillomavirus Infection and its Associated Cervical Lesions and cancer in West African Women”. Ref. No. CRP/BFA17-01. We also thank the Agence Universitaire de la Francophonie (AUF) for the financial support. We thank also the UNESCO chaire in “Génie génétique et Biologie Moléculaire” for the technical support.

The authors declare that there is no conflict of interest regarding the publication of this article.