NK Cells in HIV-1 Infection: From Basic Science to Vaccine Strategies

NK cells play a key role in immune response against HIV infection. These cells can destroy infected cells and contribute to adequate and strong adaptive immune responses, by acting on dendritic, T, B, and even epithelial cells. Increased NK cell activity reflected by higher cytotoxic capacity, IFN-γ and chemokines (CCL3, CCL4, and CCL5) production, has been associated with resistance to HIV infection and delayed AIDS progression, demonstrating the importance of these cells in the antiviral response. Recently, a subpopulation of NK cells with adaptive characteristics has been described and associated with lower HIV viremia and control of infection. These evidences, together with some degree of protection shown in vaccine trials based on boosting NK cell activity, suggest that these cells can be a feasible option for new treatment and vaccination strategies to overcome limitations that, classical vaccination approaches, might have for this virus. This review is focus on the NK cells role during the immune response against HIV, including all the effector mechanisms associated to these cells; in addition, changes including phenotypic, functional and frequency modifications during HIV infection will be pointed, highlighting opportunities to vaccine development based in NK cells effector functions

THE INTERLEUKIN 21 (IL 21)/ MICRORNA-29 (MIR-29) AXIS IS ASSOCIATED WITH NATURAL RESISTANCE TO HIV-1 INFECTION

BACKGROUND: Interleukin-21 (IL-21) modulates HIV-1 infection through the elicitation of different antiviral mechanisms, including Th17 lineage commitment and induction of microRNA (miR)-29, a miRNA endowed with anti-HIV activity. As miR-29 expression is significantly increased in HIV-1-exposed seronegative individuals (HESNs), we investigated the role of miR-29/IL21 axis in the natural control of HIV-1 infection. METHODS: Analyses were performed in two cohorts of sexually-exposed HESNs, one from Italy and another one from Colombia. Overall the two cohorts included 22 HESNs and 22 HIV-unexposed healthy controls (HCs) whose PBMCs were in vitro infected with an R5-tropic HIV-1Ba-L strain (Italian cohort) and an HIV-1-IIIB X4-tropic HIV-1 (Colombian cohort). Seven days post HIV-1 infection we evaluated: 1) p24 production (ELISA); 2) IL-21+/CD4+ and IL-17+/CD4+ T lymphocytes (FACS); 3) IL-17 concentration in supernatants (ELISA); and 4) IL-6, IL-17, and IL-21 mRNA and miR-29a, b, c expression by CD4+ T lymphocytes and PBMCs as well as perforin and granzymes in PBMCs (qPCR). The same analyses were performed on the 19 HIV-infected partners (HIV+). RESULTS: At baseline IL-6 expression alone was increased in HESNs compared to HCs. Thus, IL-21+/CD4+ and IL-17+/CD4+ T lymphocytes, as well as IL-21 and IL-17 expression and production were significantly augmented in HESNs compared to HCs. Interestingly, IL-21 upregulation correlated with a significantly increased expression of miR-29a, b, c in Italian cohort and with a reduced susceptibility to in vitro HIV-1 infection in HESNs alone. Differences in the expression of perforin and granzymes were observed in the Colombian cohort. CONCLUSIONS: The IL-21/miR-29 axis is upregulated by HIV-1 infection in HESNs suggesting its involvement in the natural resistance to HIV-1 infection in these individuals. Approaches that exogenously increase IL-21 production or prompt pre-existing cellular IL-21 reservoir could confine the magnitude of the initial HIV-1 infection

Influence of Genetic Polymorphism Towards Pulmonary Tuberculosis Susceptibility

Tuberculosis (TB) is still remains the major threat for human health worldwide. Several case-control, candidate-gene, family studies and genome-wide association studies (GWAS) suggested the association of host genetic factors to TB susceptibility or resistance in various ethnic populations. Moreover, these factors modulate the host immune responses to tuberculosis. Studies have reported genetic markers to predict TB development in human leukocyte antigen (HLA) and non-HLA genes like killer immunoglobulin-like receptor (KIR), toll-like receptors (TLRs), cytokine/chemokines and their receptors, vitamin D receptor (VDR) and SLC11A1 etc. Highly polymorphic HLA loci may influence antigen presentation specificities by modifying peptide binding motifs. The recent meta-analysis studies revealed the association of several HLA alleles in particular class II HLA-DRB1 with TB susceptibility and valuable marker for disease development especially in Asian populations. Case-control studies have found the association of HLA-DR2 in some populations, but not in other populations, this could be due to an ethnic specific association of gene variants. Recently, GWAS conducted in case-control and family based studies in Russia, Chinese Han, Morocco, Uganda and Tanzania revealed the association of genes such as ASAP1, Alkylglycerol monooxygenase (AGMO), Forkhead BoxP1 (FOXP1), C-terminal domain phosphatase 1 (UBLCP1) and intergenic SNP rs932347C/T with TB. Whereas, SNP rs10956514A/G were not associated with TB in western Chinese Han and Tibetan population. In this review, we summarize the recent findings of genetic variants with susceptibility/resistance to TB

Implication de DC-SIGN et DC-SIGNR dans la transmission mère-enfant du VIH-1

La transmission mère-enfant du VIH-1 (TME) représente le principal mode d’infection chez l’enfant et se produit durant la grossesse (in utero, IU), l’accouchement (intrapartum, IP) ou l’allaitement (postpartum, PP). Les mécanismes qui sous-tendent le passage du VIH-1 à travers le placenta et les muqueuses intestinales du nouveau-né sont encore très peu décrits. « Dendritic cell-specific ICAM-grabbing non-integrin » (DC-SIGN) et son homologue DC-SIGN « related » (DC-SIGNR) sont des récepteurs d’antigènes exprimés au niveau du placenta et capables de capter et de transmettre le VIH-1 aux cellules adjacentes. Ils pourraient donc participer au passage trans placentaire du VIH-1 et le polymorphisme génétique affectant l’expression ou modifiant l’interaction avec le virus aurait une influence sur la TME du VIH-1. Afin d’explorer cette hypothèse, nous avons procédé à une analyse exhaustive du polymorphisme de DC-SIGN et DC-SIGNR dans la population du Zimbabwe. Par la suite, nous avons déterminé l’association entre le polymorphisme de DC-SIGN et DC-SIGNR et la TME du VIH-1 dans une cohorte d’enfants nés de mères VIH-positives à Harare, au Zimbabwe. Enfin, nous avons défini l’impact fonctionnel des mutations associées. Les enfants homozygotes pour les haplotypes H1 et H3 dans le gène de DC-SIGNR sont 4 à 6 fois plus à risque de contracter le VIH-1 par voie IU et IP. H1 et H3 contiennent la mutation du promoteur p-198A et la mutation de l’intron 2, int2-180A, et des études fonctionnelles nous ont permis de démontrer que p-198A diminue l’activité transcriptionnelle du promoteur de DC-SIGNR et l’expression des transcrits d’ARNm dans le placenta, alors que int2-180A modifie le répertoire d’isoformes de DC-SIGNR vers une proportion diminuée d’isoformes membranaires. Les enfants porteurs des haplotypes H4 et H6 de DC-SIGN sont 2 à 6 fois plus à risque de contracter le VIH-1 par voie IU. Ces haplotypes contiennent deux mutations du promoteur (p-336T/C et p-201C/A) et quatre mutations codant pour un changement d’acide aminé dans l’exon 4 (R198Q, E214D, R221Q ou L242V) associées à un risque augmenté de transmission IU, IP et PP du VIH-1. Des études fonctionnelles ont démontré que les mutations du promoteur diminuent l’expression de DC-SIGN dans les macrophages placentaires. Toutefois, l’exposition IU au VIH-1 module le niveau d’expression de DC-SIGN, résultant en des niveaux d’expression similaires entre les macrophages des porteurs des allèles sauvages et mutés. Les mutations de l’exon 4 augmentent l’affinité de DC-SIGN pour le VIH-1 et sa capacité à capturer et à transmettre le virus aux lymphocytes T, favorisant possiblement la dissémination du VIH-1 à travers le placenta. L’association entre les mutations de DC-SIGN et la transmission IP et PP du VIH-1 suggèrent qu’il aurait aussi un rôle à jouer dans les muqueuses intestinales de l’enfant. Notre étude démontre pour la première fois l’implication de DC-SIGN et DC-SIGNR dans la TME du VIH-1. L’augmentation des capacités de capture et de transmission de DC-SIGN résulte en une susceptibilité accrue de l’enfant à l’infection au VIH-1 et concorde avec un rôle dans la dissémination transplacentaire. Toutefois, la diminution préférentielle des transcrits membranaires de DC-SIGNR au placenta augmente la TME du VIH-1 et laisse croire à son implication via un autre mécanisme. Ces mécanismes pourraient aussi s’appliquer à d’autres pathogènes reconnus par DC-SIGN et DC-SIGNR et transmis de la mère à l’enfant.Mother-to-child transmission (MTCT) is the main cause of HIV-1 infection in children worldwide. MTCT of HIV-1 can occur during pregnancy (in utero, IU), delivery (intrapartum, IP) or breastfeeding (postpartum, PP). Dendritic cell-specific ICAM-grabbing non-integrin (DC-SIGN) and its homolog DC-SIGN related (DC-SIGNR) are attachment receptors for HIV-1 and are expressed in the placenta. They have been implicated in viral capture and transmission to T cells. To investigate the potential role of DC-SIGN and DC-SIGNR in MTCT of HIV-1, we carried out a genetic association study in a well-characterized cohort of 197 HIV-infected mothers and their infants recruited in Harare, Zimbabwe. Infants harbouring two copies of DC-SIGNR H1 and/or H3 haplotypes (H1-H1, H1-H3, H3-H3) had a 4-fold increased risk of IU and 6-fold increased risk of IP HIV-1 infection after adjusting for a number of maternal factors. The implicated H1 and H3 haplotypes share two single nucleotide polymorphisms (SNPs) in promoter region (p-198A) and intron 2 (int2-180A) that were associated with increased risk of both IU and IP HIV-1 infection. The promoter variant reduced transcriptional activity in vitro. In homozygous H1 infants bearing both the p-198A and int2-180A mutations, we observed a 4-fold decrease in the level of placental DC-SIGNR transcripts, disproportionately affecting the expression of membrane-bound isoforms compared to infant noncarriers. Infants carrying H4 and H6 haplotypes in DC-SIGN gene were more likely to be HIV-1-infected during pregnancy. These haplotypes contain promoter variants (p-336T/C and p-201C/A) and exon 4 variants (R198Q, E214D, R221Q and L242V) that were all significantly associated with increased risk of MTCT of HIV-1. Compared with wild-type sequence, the promoter variants reduced both the DC-SIGN transcription in vitro and expression (2-fold) in placental macrophages of HIV-1-unexposed infants. However, in HIV-1-exposed infants, the level of DC-SIGN expression in placental macrophages was similar in infants carrying either the promoter wild-type or variant sequences. Exon 4 variants increased HIV-1 capture and transmission to T cells in vitro. Association between DC-SIGN SNPs and HIV-1 IP and PP infection also suggests that DC-SIGN plays an important role in intestinal mucosa. This is the first study reporting on functional impact of DC-SIGN and DC-SIGNR natural polymorphisms on HIV-1 transmission from mother-to-child. Decreased levels of expression of membrane DC-SIGNR isoforms at the placental endothelial cell surface increased child susceptibility to HIV-1. Presence of DC-SIGN variants increasing its affinity for the virus augmented child susceptibility to HIV-1 and may favour viral dissemination across the placental barrier. This study provides compelling evidence to support an important role of DC-SIGN and DC-SIGNR in various modes of MTCT of HIV-1 and shed light on the possible mechanisms involved in HIV-1 passage from mother-to-infant. These findings raise the possibility that similar mechanisms may operate with other human pathogens known to interact with DC-SIGN and DC-SIGNR

Genetic control of alphavirus pathogenesis

Alphaviruses, members of the positive-sense, single-stranded RNA virus family Togaviridae, represent a re-emerging public health concern worldwide as mosquito vectors expand into new geographic ranges. Members of the alphavirus genus tend to induce clinical disease characterized by rash, arthralgia, and arthritis (chikungunya virus, Ross River virus, and Semliki Forest virus) or encephalomyelitis (eastern equine encephalitis virus, western equine encephalitis virus, and Venezuelan equine encephalitis virus), though some patients who recover from the initial acute illness may develop long-term sequelae, regardless of the specific infecting virus. Studies examining the natural disease course in humans and experimental infection in cell culture and animal models reveal that host genetics play a major role in influencing susceptibility to infection and severity of clinical disease. Genome-wide genetic screens, including loss of function screens, microarrays, RNA-sequencing, and candidate gene studies, have further elucidated the role host genetics play in the response to virus infection, with the immune response being found in particular to majorly influence the outcome. This review describes the current knowledge of the mechanisms by which host genetic factors influence alphavirus pathogenesis and discusses emerging technologies that are poised to increase our understanding of the complex interplay between viral and host genetics on disease susceptibility and clinical outcome