Association of maternal KIR gene content polymorphisms with reduction in perinatal transmission of HIV-1

PLoS ONE, Volume 13, No. 1, Year 2018

Interprétation

The role of killer cell immunoglobulin-like receptors (KIRs) in the transmission of HIV-1 has not been extensively studied. Here, we investigated the association of KIR gene content polymorphisms with perinatal HIV-1 transmission. The KIR gene family comprising 16 genes was genotyped in 313 HIV-1 positive Kenyan mothers paired with their infants. Gene content polymorphisms were presented as presence of individual KIR genes, haplotypes, genotypes and KIR gene concordance. The genetic data were analyzed for associations with perinatal transmission of HIV. There was no association of infant KIR genes with perinatal HIV-1 transmission. After adjustment for gravidity, viral load, and CD4 cell count, there was evidence of an association between reduction in perinatal HIV-1 transmission and the maternal individual KIR genes KIR2DL2 (adjusted OR = 0.50; 95% CI: 0.24–1.02, P = 0.06), KIR2DL5 (adjusted OR = 0.47; 95% CI: 0.23–0.95, P = 0.04) and KIR2DS5 (adjusted OR = 0.39; 95% CI: 0.18–0.80, P = 0.01). Furthermore, these maternal KIR genes were only significantly associated with reduction in perinatal HIV transmission in women with CD4 cell count 350 cells/ μl and viral load <10000 copies/ml. Concordance analysis showed that when both mother and child had KIR2DS2, there was less likelihood of perinatal HIV-1 transmission (adjusted OR = 0.44; 95% CI: 0.20–0.96, P = 0.039). In conclusion, the maternal KIR genes KIR2DL2, KIR2DL5, KIR2DS5, and KIR2DS2 were associated with reduction of HIV-1 transmission from mother to child. Furthermore, maternal immune status is an important factor in the association of KIR with perinatal HIV transmission. The present study used samples from mothers and their infants from an epidemiological investigation of the relationship between placental malaria (PM) and perinatal transmission of HIV-1 [vertical transmission (VT study)] that was carried out in western Kenya between 1996 and 2001 [32, 35]. The Luo is the dominant ethnic group in the study area. During the VT study period, the prevalence of infections in pregnant women attending antenatal clinic was about 25% for HIV-1 and 20% for P. falciparum, respectively [36]. In the VT project, women were enrolled if they had singleton uncomplicated pregnancies of at least 32 weeks gestation and no known underlying chronic illnesses [32]. Information on reproductive history, socio-demographics, heath/clinical status, and malaria treatment was collected at enrollment and delivery. Blood samples were collected from mothers at enrollment, delivery, and one month postpartum for HIV diagnosis, HIV viral load, CD4 count, malaria diagnosis, and hemoglobin level determination. In addition, infants were followed up and blood samples collected monthly were used for HIV diagnosis. In the VT epidemiological study, HIV-positive women were given enrollment priority; while among HIV-negative women, women with PM were given enrollment priority. In total, 269 HIV-negative and 829 HIV-positive pregnant women were originally enrolled in the VT epidemiological study. For this host genetics study, we analyzed blood samples from 313 HIV-positive mothers paired with their infants for KIR gene content polymorphisms, based on availability of mother-infant paired samples. Counseling was provided to all women before and after HIV testing. At the time of the VT study (1996–2001), the Kenyan Ministry of Health recommended breastfeeding regardless of HIV status, and access to zidovudine or nevirapine was by then neither recommended by the Kenyan MOH nor available [37]. Written informed consent for participation in the study was obtained from the mothers for themselves and their infants. Study methods of the VT project, including the host genetics tests and analysis described here, were approved by the Kenya Medical Research Institute Ethical Review Committee, Nairobi, Kenya and the Institutional Review Board of the Centers for Disease Control and Prevention, Atlanta, USA. Maternal HIV status was determined based on a combination of initial testing with Sero Strip HIV-1/2 (Saliva Diagnostic Systems, New York, USA) and confirmation with Capillus HIV-1/HIV-2 test (Cambridge Diagnostics, Cambridge, UK). Infant HIV status was monitored monthly by DNA polymerase chain reaction (PCR) using gpM-Z primers. Maternal CD4 cell count was determined using fluorescent-activated cell sorting analysis (FACScan, Becton Dickinson, San Jose, California, USA) based on manufacturer instructions. Maternal HIV-1 viral load at delivery was measured using the Roche Amplicor HIV-1 monitor test versions 1.0 and 1.5, respectively (Roche Molecular Systems, Branchburg, New Jersey, USA)[32]. Thick smears made from placental and peripheral blood of mothers were stained with Giemsa and examined by microscopy. The number of asexual parasites/300 leukocytes was counted. Parasite density was estimated assuming 8000 leukocytes/μl. Peripheral blood hemoglobin concentrations (g/dl) were quantified using the HemoCue system (HemoCue, Brea, California) [32]. The KIR genotyping method used in this study has been described previously [38]. Briefly, DNA was extracted from blood samples from 313 mother-infant pairs using the QIAamp DNA blood mini kit (Qiagen, Valencia, California, USA). KIR genotyping for 16 KIR genes was carried out using KIRSSO genotyping test (One Lambda Inc., Canoga Park, California, USA) based on the manufacturer instructions. The results were read on a Luminex 200 IS (Luminex Corp., Austin, Texas, USA). The presence of individual KIR genes was determined using HLA Fusion Beta software (One Lambda Inc., Canoga Park, California, USA). Positive control DNA samples with different profiles of KIR gene content from the International Histocompatibility Working Group (IHWG) were used in all experiments. Infants were considered to be perinatally infected with HIV if they had two or more consecutive HIV-positive PCR tests, with the first positive PCR at or before 4 months of age[32]. Mothers of perinatally infected infants were classified as “transmitters” and those of uninfected infants as “non-transmitters.” Mothers of infants who acquired HIV at or after 5 months of age (considered postnatally acquired HIV) were also included in the analysis as non-transmitters [32]. Placental malaria was categorized into low (1–9999 parasites/μl) or high (≥ 10 000 parasites/μl) density per the parallel VT epidemiological study [32]. CD4 cell count was grouped as ≤ 200, 200–499, and ≥ 500cells/μl and viral load as <1000, 1000–9999 and ≥ 10000 copies/ml. Gravidity was divided into primi- or secundigradvida versus multigravida to allow assessment of possible differences in immunological environment between early and later pregnancies [35, 39]. KIR gene content polymorphisms were assessed in various ways: (1) the presence of 16 individual KIR genes [40]; (2) KIR haplotype A (presence of KIR3DL3, KIR2DL3, KIR2DL1, KIR2DP1, KIR3DP1, KIR2DL4, KIR3DL1, KIR2DS4 and KIR3DL2 only) and haplotype B (presence of KIR2DL1, KIR2DL2, KIR2DL4, KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5, KIR2DS5, KIR2DP1, KIR3DL2, KIR3DL3, KIR3DS1 and KIR3DP1) [41–43]; and (3) KIR genotypes AA, AB and BB. Genotype AA includes individuals with KIR3DL3, KIR2DL3, KIR2DL1, KIR2DP1, KIR3DP1, KIR2DL4, KIR3DL1, KIR2DS4, and KIR3DL2 while genotype BB comprises individuals without KIR2DL1, KIR2DL3, KIR3DL1 and KIR2DS4 [38]. Individuals not classified as either genotype AA or BB were regarded as genotype AB [44]. KIR concordance was defined as mothers and their infants having the same KIR gene content for single genes, haplotypes or genotypes. Statistical analyses compared HIV-transmitting mothers to those who did not transmit HIV in terms of characteristics of the mothers, characteristics of the babies, and KIR gene content of both mothers and babies. To determine whether characteristics of mothers or babies affected HIV transmission in unadjusted analyses, exact Chi-square tests were used for categorical characteristics, and exact Wilcoxon tests were used for other characteristics. For all other comparisons, logistic regression models were used. Due to sparse data issues, the Firth likelihood penalty was used for logistic regression models where possible [45]. If the model using Firth penalty did not converge, exact logistic regression was used. Both univariable and multivariable models were used to assess the relationship between HIV transmission status and KIR gene content of mothers or infants, where KIR gene content included single genes, genotype and haplotype. Based on the number of HIV transmitters, it was determined that multivariable models should control for no more than three variables to reduce the possibility of over fitting the data. Gravidity (<3 vs. ≥3), viral load (<10,000 copies/ml vs. ≥10,000 copies/ml), and CD4 count (<350 cells/ul vs. ≥350 cells /ul) were controlled for in the multivariable models as these were known predictors of MTCT of HIV [5, 46, 47]. Concordance models assessed whether a mother and child having the same single genes, haplotype, or genotype, affected HIV transmission. Again, both univariable and multivariable models were fit, and multivariable models controlled for gravidity, CD4 count, and viral load, which were categorized as mentioned above. For several single genes that appeared related to HIV transmission from mother to child, models with interaction terms were used to assess whether the relationship between KIR gene content of mothers and MTCT differed for different levels of CD4 count or viral load, where CD4 count and viral load were dichotomized as mentioned above. Models controlled for gravidity and were fit for CD4 count and viral load separately. The false discovery rate (FDR) was used to determine significance, controlling for multiple comparisons within each of the comparison groups separately, where comparison groups were defined by gene content type (single genes or not), whether the genes considered were from infants, mothers, or concordance between the two, and if the models used were adjusted. Two additional groups were defined for the interaction models, one group with interaction with CD4 and the other group with viral load interaction. Since there are two gene content types, three subject types, and two model types, plus two additional interaction model groups, there were 14 comparison groups for which FDR was used to determine significance individually.

Résumé de l’IA

Study Justification:

This study aimed to investigate the association between killer cell immunoglobulin-like receptor (KIR) gene content polymorphisms and perinatal transmission of HIV-1. The role of KIRs in HIV-1 transmission has not been extensively studied, and understanding this association could provide valuable insights into preventing HIV transmission from mother to child.

Highlights:

– The study analyzed the KIR gene family in 313 HIV-1 positive Kenyan mothers and their infants.
– Maternal KIR genes KIR2DL2, KIR2DL5, KIR2DS5, and KIR2DS2 were found to be associated with a reduction in perinatal HIV-1 transmission.
– These associations were significant in women with a CD4 cell count of 350 cells/μl and viral load

Force de la preuve

The strength of evidence for this abstract is 7 out of 10.
The evidence in the abstract is moderately strong, but there are some areas for improvement. The study design is well-described and the sample size is adequate. The statistical analyses used are appropriate. However, the abstract does not provide information on potential confounding factors that were controlled for in the multivariable models. Additionally, the abstract does not mention any limitations of the study or potential sources of bias. To improve the evidence, the abstract should include a discussion of potential confounders and limitations, as well as a statement on the generalizability of the findings.

Abstrait

The present study used samples from mothers and their infants from an epidemiological investigation of the relationship between placental malaria (PM) and perinatal transmission of HIV-1 [vertical transmission (VT study)] that was carried out in western Kenya between 1996 and 2001 [32, 35]. The Luo is the dominant ethnic group in the study area. During the VT study period, the prevalence of infections in pregnant women attending antenatal clinic was about 25% for HIV-1 and 20% for P. falciparum, respectively [36]. In the VT project, women were enrolled if they had singleton uncomplicated pregnancies of at least 32 weeks gestation and no known underlying chronic illnesses [32]. Information on reproductive history, socio-demographics, heath/clinical status, and malaria treatment was collected at enrollment and delivery. Blood samples were collected from mothers at enrollment, delivery, and one month postpartum for HIV diagnosis, HIV viral load, CD4 count, malaria diagnosis, and hemoglobin level determination. In addition, infants were followed up and blood samples collected monthly were used for HIV diagnosis. In the VT epidemiological study, HIV-positive women were given enrollment priority; while among HIV-negative women, women with PM were given enrollment priority. In total, 269 HIV-negative and 829 HIV-positive pregnant women were originally enrolled in the VT epidemiological study. For this host genetics study, we analyzed blood samples from 313 HIV-positive mothers paired with their infants for KIR gene content polymorphisms, based on availability of mother-infant paired samples. Counseling was provided to all women before and after HIV testing. At the time of the VT study (1996–2001), the Kenyan Ministry of Health recommended breastfeeding regardless of HIV status, and access to zidovudine or nevirapine was by then neither recommended by the Kenyan MOH nor available [37]. Written informed consent for participation in the study was obtained from the mothers for themselves and their infants. Study methods of the VT project, including the host genetics tests and analysis described here, were approved by the Kenya Medical Research Institute Ethical Review Committee, Nairobi, Kenya and the Institutional Review Board of the Centers for Disease Control and Prevention, Atlanta, USA. Maternal HIV status was determined based on a combination of initial testing with Sero Strip HIV-1/2 (Saliva Diagnostic Systems, New York, USA) and confirmation with Capillus HIV-1/HIV-2 test (Cambridge Diagnostics, Cambridge, UK). Infant HIV status was monitored monthly by DNA polymerase chain reaction (PCR) using gpM-Z primers. Maternal CD4 cell count was determined using fluorescent-activated cell sorting analysis (FACScan, Becton Dickinson, San Jose, California, USA) based on manufacturer instructions. Maternal HIV-1 viral load at delivery was measured using the Roche Amplicor HIV-1 monitor test versions 1.0 and 1.5, respectively (Roche Molecular Systems, Branchburg, New Jersey, USA)[32]. Thick smears made from placental and peripheral blood of mothers were stained with Giemsa and examined by microscopy. The number of asexual parasites/300 leukocytes was counted. Parasite density was estimated assuming 8000 leukocytes/μl. Peripheral blood hemoglobin concentrations (g/dl) were quantified using the HemoCue system (HemoCue, Brea, California) [32]. The KIR genotyping method used in this study has been described previously [38]. Briefly, DNA was extracted from blood samples from 313 mother-infant pairs using the QIAamp DNA blood mini kit (Qiagen, Valencia, California, USA). KIR genotyping for 16 KIR genes was carried out using KIRSSO genotyping test (One Lambda Inc., Canoga Park, California, USA) based on the manufacturer instructions. The results were read on a Luminex 200 IS (Luminex Corp., Austin, Texas, USA). The presence of individual KIR genes was determined using HLA Fusion Beta software (One Lambda Inc., Canoga Park, California, USA). Positive control DNA samples with different profiles of KIR gene content from the International Histocompatibility Working Group (IHWG) were used in all experiments. Infants were considered to be perinatally infected with HIV if they had two or more consecutive HIV-positive PCR tests, with the first positive PCR at or before 4 months of age[32]. Mothers of perinatally infected infants were classified as “transmitters” and those of uninfected infants as “non-transmitters.” Mothers of infants who acquired HIV at or after 5 months of age (considered postnatally acquired HIV) were also included in the analysis as non-transmitters [32]. Placental malaria was categorized into low (1–9999 parasites/μl) or high (≥ 10 000 parasites/μl) density per the parallel VT epidemiological study [32]. CD4 cell count was grouped as ≤ 200, 200–499, and ≥ 500cells/μl and viral load as <1000, 1000–9999 and ≥ 10000 copies/ml. Gravidity was divided into primi- or secundigradvida versus multigravida to allow assessment of possible differences in immunological environment between early and later pregnancies [35, 39]. KIR gene content polymorphisms were assessed in various ways: (1) the presence of 16 individual KIR genes [40]; (2) KIR haplotype A (presence of KIR3DL3, KIR2DL3, KIR2DL1, KIR2DP1, KIR3DP1, KIR2DL4, KIR3DL1, KIR2DS4 and KIR3DL2 only) and haplotype B (presence of KIR2DL1, KIR2DL2, KIR2DL4, KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5, KIR2DS5, KIR2DP1, KIR3DL2, KIR3DL3, KIR3DS1 and KIR3DP1) [41–43]; and (3) KIR genotypes AA, AB and BB. Genotype AA includes individuals with KIR3DL3, KIR2DL3, KIR2DL1, KIR2DP1, KIR3DP1, KIR2DL4, KIR3DL1, KIR2DS4, and KIR3DL2 while genotype BB comprises individuals without KIR2DL1, KIR2DL3, KIR3DL1 and KIR2DS4 [38]. Individuals not classified as either genotype AA or BB were regarded as genotype AB [44]. KIR concordance was defined as mothers and their infants having the same KIR gene content for single genes, haplotypes or genotypes. Statistical analyses compared HIV-transmitting mothers to those who did not transmit HIV in terms of characteristics of the mothers, characteristics of the babies, and KIR gene content of both mothers and babies. To determine whether characteristics of mothers or babies affected HIV transmission in unadjusted analyses, exact Chi-square tests were used for categorical characteristics, and exact Wilcoxon tests were used for other characteristics. For all other comparisons, logistic regression models were used. Due to sparse data issues, the Firth likelihood penalty was used for logistic regression models where possible [45]. If the model using Firth penalty did not converge, exact logistic regression was used. Both univariable and multivariable models were used to assess the relationship between HIV transmission status and KIR gene content of mothers or infants, where KIR gene content included single genes, genotype and haplotype. Based on the number of HIV transmitters, it was determined that multivariable models should control for no more than three variables to reduce the possibility of over fitting the data. Gravidity (<3 vs. ≥3), viral load (<10,000 copies/ml vs. ≥10,000 copies/ml), and CD4 count (<350 cells/ul vs. ≥350 cells /ul) were controlled for in the multivariable models as these were known predictors of MTCT of HIV [5, 46, 47]. Concordance models assessed whether a mother and child having the same single genes, haplotype, or genotype, affected HIV transmission. Again, both univariable and multivariable models were fit, and multivariable models controlled for gravidity, CD4 count, and viral load, which were categorized as mentioned above. For several single genes that appeared related to HIV transmission from mother to child, models with interaction terms were used to assess whether the relationship between KIR gene content of mothers and MTCT differed for different levels of CD4 count or viral load, where CD4 count and viral load were dichotomized as mentioned above. Models controlled for gravidity and were fit for CD4 count and viral load separately. The false discovery rate (FDR) was used to determine significance, controlling for multiple comparisons within each of the comparison groups separately, where comparison groups were defined by gene content type (single genes or not), whether the genes considered were from infants, mothers, or concordance between the two, and if the models used were adjusted. Two additional groups were defined for the interaction models, one group with interaction with CD4 and the other group with viral load interaction. Since there are two gene content types, three subject types, and two model types, plus two additional interaction model groups, there were 14 comparison groups for which FDR was used to determine significance individually.

Matériaux

N/A

Innovations

Based on the provided information, it appears that the study investigated the association between maternal killer cell immunoglobulin-like receptor (KIR) gene content polymorphisms and perinatal transmission of HIV-1. The study found that certain maternal KIR genes, including KIR2DL2, KIR2DL5, KIR2DS5, and KIR2DS2, were associated with a reduction in perinatal HIV-1 transmission. These associations were observed in women with a CD4 cell count of 350 cells/μl or higher and a viral load of less than 10,000 copies/ml. Additionally, when both the mother and child had the KIR2DS2 gene, there was a lower likelihood of perinatal HIV-1 transmission.

It is important to note that this study focused on understanding the genetic factors associated with perinatal HIV-1 transmission and did not directly address innovations to improve access to maternal health. To identify potential innovations for improving access to maternal health, it would be necessary to consider other research studies, initiatives, or interventions specifically targeting this area.

AI Innovations Description

The study investigated the association between killer cell immunoglobulin-like receptor (KIR) gene content polymorphisms and perinatal transmission of HIV-1. The findings showed that certain maternal KIR genes, specifically KIR2DL2, KIR2DL5, KIR2DS5, and KIR2DS2, were associated with a reduction in perinatal HIV-1 transmission. This association was observed in women with a CD4 cell count of 350 cells/μl or higher and a viral load of less than 10,000 copies/ml. Additionally, when both the mother and child had the KIR2DS2 gene, there was a lower likelihood of perinatal HIV-1 transmission.

The study used samples from HIV-positive Kenyan mothers and their infants. The mothers were enrolled in the study if they had uncomplicated pregnancies of at least 32 weeks gestation and no known chronic illnesses. Data on reproductive history, socio-demographics, health/clinical status, and malaria treatment were collected. Blood samples were taken from the mothers at enrollment, delivery, and one month postpartum for HIV diagnosis, viral load measurement, CD4 cell count, and malaria diagnosis. Infants were followed up, and monthly blood samples were collected for HIV diagnosis.

The KIR gene content polymorphisms were assessed in various ways, including the presence of individual KIR genes, KIR haplotypes A and B, and KIR genotypes AA, AB, and BB. Statistical analyses were conducted to compare HIV-transmitting mothers with non-transmitting mothers in terms of characteristics of the mothers, characteristics of the babies, and KIR gene content of both mothers and babies. Logistic regression models were used to assess the relationship between HIV transmission status and KIR gene content, controlling for variables such as gravidity, viral load, and CD4 count.

In conclusion, the study suggests that maternal KIR gene content polymorphisms may play a role in reducing perinatal transmission of HIV-1. These findings highlight the importance of considering maternal immune status and genetic factors in efforts to improve access to maternal health and reduce the transmission of HIV-1 from mother to child.

AI Innovations Methodology

Based on the provided information, the study investigated the association of killer cell immunoglobulin-like receptor (KIR) gene content polymorphisms with perinatal transmission of HIV-1. The study analyzed samples from 313 HIV-1 positive Kenyan mothers paired with their infants. The methodology involved genotyping the KIR gene family comprising 16 genes and analyzing the genetic data for associations with perinatal transmission of HIV-1.

To simulate the impact of these recommendations on improving access to maternal health, the following methodology can be used:

1. Data Collection: Collect data on maternal health indicators such as maternal mortality rate, access to antenatal care, skilled birth attendance, and availability of essential maternal health services in the target population.

2. Identify Innovations: Identify potential innovations that can improve access to maternal health. These innovations can include technological solutions, policy changes, community-based interventions, or healthcare system improvements.

3. Define Outcome Measures: Define outcome measures to assess the impact of the innovations on improving access to maternal health. These measures can include changes in maternal mortality rate, increase in antenatal care coverage, improvement in skilled birth attendance, and enhanced availability of essential maternal health services.

4. Simulation Model Development: Develop a simulation model that incorporates the identified innovations and their potential impact on the outcome measures. The model should consider factors such as population demographics, healthcare infrastructure, resource availability, and the effectiveness of the innovations.

5. Data Analysis: Use the simulation model to analyze the impact of the innovations on improving access to maternal health. This can be done by comparing the baseline scenario (without the innovations) to the simulated scenario (with the innovations) and assessing the changes in the outcome measures.

6. Sensitivity Analysis: Conduct sensitivity analysis to assess the robustness of the simulation results. This involves varying the input parameters of the model to test the sensitivity of the outcomes to different scenarios and assumptions.

7. Policy Recommendations: Based on the simulation results, provide policy recommendations on the implementation of the identified innovations to improve access to maternal health. Consider factors such as feasibility, cost-effectiveness, scalability, and sustainability of the innovations.

By following this methodology, policymakers and stakeholders can gain insights into the potential impact of innovations on improving access to maternal health and make informed decisions on their implementation.

Auteur

Dima Health

Statistics:

Citations: 7

Identifiers:

DOI: 10.1371/journal.pone.0191733

Research Areas:

Community Interventions, Genetics and Genomics, Health System and Policy, Infectious Diseases, Maternal Access, Maternal and Child Health, Sexual and Reproductive Health, Social Determinants

Study Countries:

Kenya

Study Design:

Cross Sectional Study

Participants Gender:

Female

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