KIR2DL1 gene is a surrogate marker of protection against infection-related hospitalization among HIV-1 unexposed versus exposed uninfected infants in Cameroon.

BACKGROUND: HIV-exposed uninfected infants (HEU) appear more vulnerable to infections compared to their HIV-unexposed uninfected (HUU) peers, generally attributed to poor passive immunity acquired from the mother. This may be due to some genetic factors that could alter the immune system. We thus sought to determine the distribution of Killer Cell Immunoglobulin-Like Receptors (KIRs) genes in HEU versus HUU and study their associations with the occurrence of infection-related hospitalization. METHODS: A cohort study was conducted from May 2019 to April 2020 among HEU and HUU infants, including their follow-up at weeks 6, 12, 24, and 48, in reference pediatric centers in Yaoundé-Cameroon. The infant HIV status and infections were determined. A total of 15 KIR genes were investigated using the sequence-specific primer polymerase chain reaction (PCR-SSP) method. The KIR genes that were significantly associated with HIV-1 status (HEU and HUU) were analyzed for an association with infection-related hospitalizations. This was only possible if, and to the extent that, infection-related hospitalizations varied significantly according to status. Multivariate logistic regression analyses were conducted to determine the association between KIR gene content variants and HIV status, while considering a number of potential confounding factors. Furthermore, the risk was quantified using relative risk, odds ratio, and a 95% confidence interval. The Fisher exact test was employed to compare the frequency of occurrences. A p-value of less than 0.05 was considered statistically significant. RESULTS: In this cohort, a total of 66 infants participated, but only 19 acquired infections requiring hospitalizations (14.81%, 04/27 HUU and 38.46%, 15/39 HEU, p = 0.037). At week 48 (39 HEU and 27 HUU), the relative risk (RR) for infection-related hospitalizations was 2.42 (95% CI: 1.028-5.823) for HEU versus HUU with OR 3.59 (1.037-12.448). KIR2DL1 gene was significantly underrepresented in HEU versus HUU (OR = 0.183, 95%CI: 0.053-0.629; p = 0.003), and the absence of KIR2DL1 was significantly associated with infection-related hospitalization (p < 0.001; aOR = 0.063; 95%CI: 0.017-0.229). CONCLUSION: Compared to HUU, the vulnerability of HEU is driven by KIR2DL1, indicating the protective role of this KIR against infection and hospitalizations.

HIV-1 interaction with an O-glycan-specific bacterial lectin enhances virus infectivity and resistance to neutralization by antibodies.

Bacteria dysbiosis has been associated with an increased risk of HIV-1 transmission and acquisition. The prevalent idea is that bacteria dysbiosis compromises mucosal integrity and promotes inflammatory conditions to cause recruitment and activation of immune cells that harbor or are targeted by HIV-1. However, it is also possible that HIV-1 directly binds bacteria or bacterial products to impact virus infectivity and transmissibility. This study evaluated HIV-1 interactions with bacteria through glycan-binding lectins. The Streptococcal Siglec-like lectin SLBR-N, which is part of the fimbriae shrouding the bacteria surface and recognizes α2,3 sialyated O-linked glycans, was noted for its ability to enhance HIV-1 infectivity in the context of cell-free infection and cell-to-cell transfer. Enhancing effects were recapitulated with O-glycan-binding plant lectins, signifying the importance of O-glycans. Conversely, N-glycan-binding bacterial lectins FimH and Msl had no effect. SLBR-N was demonstrated to capture and transfer infectious HIV-1 virions, bind to O-glycans on HIV-1 Env, and increase HIV-1 resistance to broadly neutralizing antibodies targeting different regions of Env. Hence, this study highlights the potential contribution of O-glycans in promoting HIV-1 infection through the exploitation of O-glycan-binding lectins from commensal bacteria at the mucosa.

HIV-1 interaction with an O-glycan-specific bacterial lectin enhances virus infectivity and resistance to neutralizing antibodies.

Bacteria dysbiosis and its accompanying inflammation or compromised mucosal integrity is associated with an increased risk of HIV-1 transmission. However, HIV-1 may also bind bacteria or bacterial products to impact infectivity and transmissibility. This study evaluated HIV-1 interactions with bacteria through glycan-binding lectins. The Streptococcal Siglec-like lectin SLBR-N, a part of the fimbriae shrouding the bacteria surface that recognizes α2,3 sialyated O-linked glycans, was noted for its ability to enhance HIV-1 infectivity in the context of cell-free infection and cell-to-cell transfer. Enhancing effects were recapitulated with O-glycan-binding plant lectins, signifying the importance of O-glycans. N-glycan-binding bacterial lectins FimH and Msl had no effect. SLBR-N was demonstrated to capture and transfer infectious HIV-1 virions, bind to O-glycans on HIV-1 Env, and increase HIV-1 resistance to neutralizing antibodies targeting different regions of Env. This study highlights the potential contribution of O-glycan-binding lectins from commensal bacteria at the mucosa in promoting HIV-1 infection.

Killer-Cell Immunoglobulin-Like Receptors (KIR) in HIV-Exposed Infants in Cameroon.

The biological reason(s) behind persistent mother-to-child transmission (MTCT) of HIV (albeit at reduced rate compared to the preantiretroviral therapy era) in spite of the successful implementation of advanced control measures in many African countries remains a priority concern to many HIV/AIDS control programs. This may be partly due to differences in host immunogenetic factors in highly polymorphic regions of the human genome such as those encoding the killer-cell immunoglobulin-like receptor (KIR) molecules which modulate the activities of natural killer cells. The primary aim of this study was to determine the variants of KIR genes that may have a role to play in MTCT in a cohort of infants born to HIV-infected mothers in Yaoundé, Cameroon. We designed a cross-sectional study to molecularly determine the frequencies of 15 KIR genes in 14 HIV-exposed infected (HEI), 39 HIV-exposed/uninfected (HEU), and 27 HIV-unexposed/uninfected (HUU) infants using the sequence specific primer polymerase chain reaction (PCR-SSP) method. We found that all 15 KIR genes were present in our cohort. The frequency of KIR2DL1 was significantly higher in the unexposed (control) group than in the HIV-exposed group (OR = 0.22, P = 0.006). Stratifying analysis by infection status but focusing only on exposed infants revealed that KIR2DL5, KIR2DS1, and KIR2DS5 were significantly overrepresented among the HIV-exposed/uninfected compared to infected infants (OR = 0.20, P = 0.006). Similarly, the frequencies of KIR2DS1, KIR2DS5, and KIR2DL5 were significantly different between infants perinatally infected with HIV (HIV+ by 6 months of age) and HIV-negative infants. Our study demonstrates that KIR genes may have differential effects with regard to MTCT of HIV-1.

Variation of HLA class I (-A and -C) genes in individuals infected with hepatitis B or hepatitis C virus in Cameroon.

The Human Leucocyte Antigens (HLA) work in concert with other immune factors to modulate immunity to viral infections. Extensive variation has been reported in the genetic sequences and functions of classical HLA class I genes in many (mostly Western) populations, and several HLA associations with infectious disease outcomes have been reported. Little is known about their role in the susceptibility or resistance to hepatitis viruses in Central African populations. The aim of this study was to determine variants of two HLA class I genes (HLA-A and -C) in adults infected with hepatitis B (HBV)- or -C (HCV) virus in Cameroon. In this case-control study, a total of 169 unrelated adults comprising 68 HCV-infected, 38 HBV-infected and 63 uninfected (controls) individuals participated. Each consented participant was screened for HBV, HCV, and HIV infections and willingly donated a single blood sample for genomic DNA isolation and some clinical laboratory tests. HLA-A and HLA-C were genotyped using previously described sequence-based techniques (SBT). A total of 54 HLA alleles were identified in the study population (27 HLA-A and 27 HLA-C). HLA-A∗23:01 and HLA-C∗07:01 were the most common alleles with genotype frequencies of 31.4% and 29.3%, respectively. Hepatitis individuals were six times more likely to be HLA-A∗30:01 carriers than uninfected controls (OR = 6.30, p = 0.020 (HBV); OR = 6.21, p = 0.010 (HCV), respectively). Similarly, carriers of HLA-C∗17:01 were over-represented in the HBV-infected compared to the uninfected control group (21.9% vs. 6.4%, respectively) suggesting that this allele could play a role in the susceptibility to HBV infection. These findings demonstrate that carriers of HLA-A∗30:01 were over-represented in the hepatitis group compared to uninfected controls while HLA-C∗17:01 was completely absent in the HCV + group.

Killer Cell Immunoglobulin-Like Receptor Genotypes and Haplotypes Contribute to Susceptibility to Hepatitis B Virus and Hepatitis C Virus Infection in Cameroon.

Over 325 million people worldwide are living with hepatitis B and C viral infections and are at greater risk of developing hepatocellular carcinoma. The interactions between killer cell immunoglobulin-like receptors (KIRs) and their cognate ligands, human leukocyte antigens, modulate both infection processes and disease progression. We report here (1) genotype and haplotype variations in KIR genes in Cameroon and (2) their impact on susceptibility to hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. In 98 unrelated individuals (33 HCV+, 31 HBV+, and 34 uninfected healthy controls), we determined the presence of 15 KIR genes by polymerase chain reaction-sequence-specific primer techniques. One pseudogene and all 14 KIR genes were present. We identified 36 KIR genotypes, 5 of which have not been previously reported in public databases. Two inhibitory (KIR2DL1 and KIR2DL3) and three activating (KIR2DS4, KIR2DS2, and KIR2DS3) genes were present in all HCV-infected individuals. Similarly, KIR3DL1, KIR2DL1, and KIR2DS4 were present at 100% in the HBV+ group. Compared with uninfected healthy controls, the frequencies of KIR2DL2 and KIR3DS1 were significantly lower in the HBV+ group (p = 0.003 and p < 0.001, respectively). Conversely, KIR3DS1 was significantly overrepresented in the HCV+ group compared with controls (97.0% vs. 64.7%, respectively, p < 0.001). These results may imply that KIR3DS1 carriers were less likely to be HBV infected, but may be predisposed to HCV infection compared with uninfected controls, indicating their important role in transmission of these viruses. However, phenotypic, functional, and genomic studies to elucidate the role of these KIR genotypes and haplotypes in infection with HBV and HCV are important.