CCR5-Δ32 Deletion Research Articles

Host variation in type I interferon signaling genes (MX1), C-C chemokine receptor type 5 gene, and major histocompatibility complex class I alleles in treated HIV+ noncontrollers predict viral reservoir size.

Prior genomewide association studies have identified variation in major histocompatibility complex (MHC) class I alleles and C-C chemokine receptor type 5 gene (CCR5Δ32) as genetic predictors of viral control, especially in 'elite' controllers, individuals who remain virally suppressed in the absence of therapy. Cross-sectional genomewide association study. We analyzed custom whole exome sequencing and direct human leukocyte antigen (HLA) typing from 202 antiretroviral therapy (ART)-suppressed HIV+ noncontrollers in relation to four measures of the peripheral CD4+ T-cell reservoir: HIV intact DNA, total (t)DNA, unspliced (us)RNA, and RNA/DNA. Linear mixed models were adjusted for potential covariates including age, sex, nadir CD4+ T-cell count, pre-ART HIV RNA, timing of ART initiation, and duration of ART suppression. Previously reported 'protective' host genetic mutations related to viral setpoint (e.g. among elite controllers) were found to predict smaller HIV reservoir size. The HLA 'protective' B∗57:01 was associated with significantly lower HIV usRNA (q = 3.3 × 10-3), and among the largest subgroup, European ancestry individuals, the CCR5Δ32 deletion was associated with smaller HIV tDNA (P = 4.3 × 10-3) and usRNA (P = 8.7 × 10-3). In addition, genomewide analysis identified several single nucleotide polymorphisms in MX1 (an interferon stimulated gene) that were significantly associated with HIV tDNA (q = 0.02), and the direction of these associations paralleled MX1 gene eQTL expression. We observed a significant association between previously reported 'protective' MHC class I alleles and CCR5Δ32 with the HIV reservoir size in noncontrollers. We also found a novel association between MX1 and HIV total DNA (in addition to other interferon signaling relevant genes, PPP1CB, DDX3X). These findings warrant further investigation in future validation studies.

CCR5-Δ32 gene variant frequency in the Nigerian and Zimbabwean populations living in North Cyprus.

The cystine-cystine chemokine receptor 5 (CCR5) is the primary HIV co-receptor involved in the viral entry process into human cells. The 32 bp deletion variant within the CCR5 gene (CCR5-Δ32) plays a very important role in viral recognition and progression of AIDS. The current study was aimed at evaluating the CCR5-Δ32 gene variation frequency in Nigerian and Zimbabwean populations residing in Northern Cyprus. A total number of 211 subjects (103 Nigerians and 108 Zimbabweans) were analyzed. Nigerian population was further analyzed with respect to the three major ethnicities: Igbo, Hausa, and Yoruba. Polymerase Chain Reaction was used to determine the CCR5-Δ32 gene variant status. All studied subjects from both sampling groups were homozygous for the CCR5 wild type gene (CCR5-wt), meaning neither heterozygous nor homozygous genotypes of CCR5-Δ32 gene variant were observed. This study observed the absence of CCR5-Δ32 deletion gene in the Nigeria and Zimbabwean populations living in Northern Cyprus. These populations lack the genetic advantage over HIV infection and may also show a rapid progression towards AIDS. Additionally, these populations could impact the local gene frequency as these two populations interact more and more.

Association of CCR5Δ32 Deletion and Human Cytomegalovirus Infection With Colorectal Cancer in Tunisia.

Background and objectives: Human cytomegalovirus (HCMV) and genetic polymorphisms of the chemokine receptor 5 have been suggested as factors associated with the progression of colorectal cancer (CRC). The aim of the study was to evaluate the associations of both CCR5Δ32 genetic deletion and/or HCMV virus infection with CRC in Tunisia. Materials and methods: The association between HCMV and CRC was validated by Nested PCR technology performed for HCMV and HCMV-specific serum IgG and IgM antibodies were investigated by enzyme-linked immunosorbent assay. Experiments were carried out on 40 tumor and 35 peri-tumor tissues, 100 blood from CRC patients and on 140 blood samples from healthy subjects and finaly serum samples of 80 patients with CRC and 100 healthy individuals. A conventional PCR has been optimized for the detection of CCR5Δ32 in100 CRC patients and 100 healthy subjects. Results: Our results show that HCMV is significantly active in 93% of patients compared to 60% in controls (p < 0.0001, OR = 8.85, 95% CI: 3.82 -20.50). Compared to the healthy controls, the titers of IgG and IgM antiCMV antibodies in CRC patients were significantly higher than in healthy subjects (p value < 0,0001 for IgG and IgM). Statistical analysis revealed a lack of association between CCR5Δ32 mutation and colorectal cancer (p = 0.788, OR = 1.265, 95% CI: 0.228-7.011). Conclusion: our data confirmed that the HCMV infection was related to the development of CRC and that CRC cells may be infected more favorably by HCMV. Given the importance of the CCR5 in inflammation and therefore CRC progression, further studies still needed to evaluate CCR5 role as a potential candidate gene for CRC susceptibility under other polymorphisms.

CCR5Delta32 deletion as a protective factor in Czech first-wave COVID-19 subjects.

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease (COVID-19), has spread widely around the globe. Significant inter-individual differences have been observed during the course of the infection, which suggests that genetic susceptibility may be a contributing factor. CC chemokine receptor 5 (CCR5), which acts as a co-receptor for the entry of HIV-1 into cells, is promising candidate whose can have an influence on SARS-CoV-2 infection. A genetic mutation known as CCR5Delta32, consisting of a 32-nucleotide deletion, encodes a truncated protein that protects homozygous carriers of the deletion from HIV-1 infection. Similarly, inhibition of CCR5 seems to be protective against COVID-19. In our study, we successfully genotyped 416 first-wave SARS-CoV-2-positive infection survivors (164 asymptomatic and 252 symptomatic) for CCR5?32, comparing them with a population based sample of 2,404 subjects. We found the highest number (P=0.03) of CCR5Delta32 carriers in SARS-CoV-2-positive/COVID-19-asympto-matic subjects (23.8 %) and the lowest number in SARS-CoV-2-positive/COVID-19-symptomatic patients (16.7 %), with frequency in the control population in the middle (21.0 %). We conclude that the CCR5?32 I/D polymorphism may have the potential to predict the severity of SARS-CoV-2 infection.

Brief Report: Toll-like Receptor 9-1635A/G Polymorphism Is Associated With HIV-1 Rebound After Four Weeks of Interruption of Antiretroviral Therapy.

This study aims to analyze the association of the presence of common polymorphisms [single nucleotide polymorphisms (SNPs)] on Toll-like receptors (TLRs), such as TLR9-1635A/G, TLR2-1892A/C, TLR2-2258G/A, TLR4-899A/G, and TLR4-1196C/T, with the viral rebound after stopping antiretroviral treatment (ART). CCR5-Δ32 deletion and HLA-A/HLA-B alleles were also analyzed. Interruption of ART may be required to investigate the outcome of strategies aimed to achieve drug-free HIV remission or cure. However, interruption of ART is currently not indicated. This was a retrospective longitudinal study that included 57 long-term suppressed HIV-1-infected individuals. TLR SNPs were detected by real-time polymerase chain reaction (PCR). CCR5-Δ32 was analyzed by conventional PCR and HLA-A and HLA-B alleles by PCR-SSOP Luminex. HIV-1 RNA rebound at week 4 after treatment interruption positively correlated with pre-ART HIV-1 load (P = 0.025). The TLR9-1635AA genotype was independently associated with a higher HIV-1 rebound compared with those with AG + GG genotype (multivariate stepwise regression analysis, P = 0.004). Women had lower HIV-1 RNA load both at rebound and during the 72 weeks of follow-up compared with men (P < 0.05 at all time-points), whereas CD4 nadir and CD4 count set-point were similar according to sex. The pre-ART viral load was independently associated with the viral set-point (P = 0.001), whereas the presence of the HLA-A01 allele (P = 0.027) and the CD4 nadir (P = 0.001) were associated with the CD4 count set-point. The association of the TLR9-1635AA genotype with a higher HIV-1 rebound suggests that this SNP may affect the results from strategies requiring interruption of ART aimed to cure HIV-1 infection.

Coreceptor-Based Hematopoietic Stem Cell Gene Therapy for HIV Disease

Combination antiretroviral therapy (cART) has significantly reduced the mortality rate and morbidity, and has increased the life expectancy of the human immunodeficiency virus (HIV) infected patients. However, the current cART is incapable of eradicating viruses from the human body, and HIV remains one of the most notorious viruses mankind has ever faced. HIV-1 enters target cells through the binding of gp120 viral protein to a CD4 receptor and then to a coreceptor, C-C chemokine receptor 5 (CCR5) or C-X-C chemokine receptor type 4 (CXCR4). Individuals homozygous for a 32-bp deletion in the CCR5 allele, CCR5Δ32, are almost completely resistant to HIV-1 acquisition. Moreover, several of natural CXCR4 mutants which have been identified can reduce HIV-1 entry without impairing either ligand binding or signaling. In order to get rid of indefinite treatment for HIV patients, there is a growing interest in creating an HIV-resistant immune system through the use of CCR5 and CXCR4-modified hematopoietic stem cells (HSCs). Proof of concept for this approach has been provided in the instance of "Berlin patient" transplanted with allogeneic stem cells from a donor with homozygosity for the CCR5Δ32 deletion. Here, we review the progress of coreceptor-based HSC gene therapy for HIV disease and present new strategies.

CCR5Δ32 – A piece of protection in the inflammatory puzzle of multiple sclerosis susceptibility

BackgroundLeucocyte infiltration and activation in the central nervous system (CNS) is an important step in the pathogenesis of multiple sclerosis (MS). The Chemokine receptor 5 (CCR5) is implicated in immune cell migration and cytokine release in the CNS, and it was demonstrated to strongly contribute to CNS inflammation and damage in several models of sterile and pathogen-mediated CNS diseases. Although the inhibition of CCR5 results in a beneficial effect in experimental models of MS, conflicting results have been found about the loss-of-function variant CCR5Δ32 (rs333) in MS patients. The aim of this study was to evaluate the association of CCR5Δ32 and MS in a Brazilian case/control cohort. Patients and methods261 MS patients and 435 healthy controls were genotyped for CCR5Δ32. Allelic and genotypic frequencies were compared between patients and controls (case/control analysis), and among patients classified according to the MS clinical form (relapsing remitting versus progressive) and severity (EDSS, MSSS and progression index). Results and discussionThe CCR5Δ32 variant frequency was statistically higher in controls as compared to patients presenting European-derived ethnic background. The variant was more frequent in progressive MS as compared to RR-MS patients, and, although not statistically significant, a higher frequency of the truncated allele was observed among patients with less severe forms of MS. These findings emphasize the potential involvement of CCR5 signaling in CNS inflammation and damage in MS. ConclusionThe CCR5Δ32 deletion is a protective factor against the development and progression of MS in European-derived Brazilian patients.

Association of heterozygous CCR5Δ32 deletion with survival in HIV-infection: A cohort study

The role of a 32 base pair deletion in the CCR5 gene (CCR5Δ32) in HIV-disease progression and response to combined antiretroviral therapy (cART) is well established. However, the impact of CCR5Δ32 in the long-term survival pre-cART and after cART introduction in a large cohort of HIV-infected patients is unknown. We analyzed the association of CCR5Δ32 deletion in the long-term survival of HIV-infected patients recruited between June 1981 and October 2016 (n = 1006). Clinical and epidemiological variables were recorded and CCR5Δ32 deletion was assessed by PCR and electrophoretic analysis. The association of CCR5Δ32 deletion with the time to death was analyzed by Log-Rank tests and Cox Regression models. The CCR5 WT/Δ32 prevalence was 13.4% (n = 135). We did not find any homozygous subject for CCR5Δ32 deletion. AIDS (n = 85, 41.5%) and non-AIDS (n = 87, 42.4%) events were the main causes of 205 deaths. CCR5Δ32 deletion was independently associated with survival (p = 0.022; hazard ratio (HR): 0.572, confidence interval (CI) [0.354–0.923]), after adjusting by HIV diagnosis before 1997, age at diagnosis, being on cART, risk of transmission, nadir CD4+ T-cell counts and CDC stage C. This result was reproduced when the analysis was restricted to patients on cART (p = 0.045; HR: 0.530 [0.286–0.985]). These results confirm the protective role of CCR5Δ32, and extend it to the long-term survival in a large cohort of HIV-infected patients. Beyond its antiviral effect, CCR5Δ32 enhanced the long-term survival of patients on cART.

Disease Resistance and the Definition of Genetic Enhancement.

Recent gene editing experiments carried out in human embryos have raised the question of whether interventions like the introduction of a CCR5-Δ32 deletion, which could provide heritable resistance to HIV infection, ought to be considered enhancements. Many authors have used the term “enhancement” in different ways, some based on patients’ biomedical outcomes and others on their social context. These classifications are often considered overly imprecise. Nevertheless, the concept of “enhancement” could affect the ways in which these applications are regulated in different jurisdictions, the availability of coverage by insurers or public health care, and the force of public opinion in shaping future policy on gene editing. In order to ethically situate resistance to communicable disease with reference to other techniques, this article provides an overview of its similarities and differences with disease gene therapy in embryos, gene therapy in consenting adults, and vaccination. In discussing key ethical features of CCR5-Δ32 deletion (including its frequency in various populations, biological mechanism, benefits for individuals, and use in previous clinical trials) we offer some potential guideposts for the continuing discussion on how to classify “enhancements” in the age of CRISPR gene editing.

Genetic Modulation Therapy Through Stem Cell Transplantation for Human Immunodeficiency Virus 1 Infection

Highly active anti-retroviral treatment has changed the dimensions of the outcomes for patients suffering from human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). However, HIV infection is still an ailment which is spreading throughout the world extensively. Given the confinements of the present restorative methodologies and the non-availability of any strategic vaccination against HIV, there is a squeezing need to build a therapeutic treatment.Viral tropism for HIV includes CD4+ cells, macrophages, and microglial cells, and it is through binding with co-receptors C-C chemokine receptor type 5 (CCR5) and C-X-C chemokine receptor type 4 (CXCR4). While these cell types are present in all individuals, there are rare cases that stayed uninfected even after getting exposed to an overwhelming load of HIV. Research revealed a homozygous 32-base pair deletion (Δ32/Δ32) in CCR5. After careful consideration, a hypothesis was proposed a few years back that a cure for HIV disease is possible, through hematopoietic stem cells transplantation from a donor homozygous for the CCR5-Δ32 deletion.Hematopoietic stem cell (HSC) based quality treatment may serve as a promising tool as these perpetual, self-renewing progenitor cells could be modified to oppose HIV infection. If done properly, the changed HSCs would offer the permanent creation of genetically modified cells that are resistant to HIV infection and/or have improved hostility to viral action which will eventually clear the contaminated cells.The purpose of this review is to concentrate on two facets of HSC genetic treatment for potentially life-threatening HIV infection: building HIV-resistant cells and designing cells that can target HIV disease. These two strategic approaches can be the frontline of a quality treatment plan against HIV infection and, as an individual treatment or a combination thereof, has been proposed to possibly destroy HIV altogether.

Can research at the end of life be a useful tool to advance HIV cure?

OPINION Can research at the end of life be a useful tool to advance HIV cure? Sara Gianella a , Jeff Taylor b , Timothy R. Brown c , Andy Kaytes b , Cristian L. Achim a , David J. Moore a , Susan J. Little a , Ronald J. Ellis a and Davey M. Smith a,d AIDS 2017, 31:1–4 Keywords: end of life, eradication, HIV cure, last gift, legacy, peri-mortem research model, research Modern antiretroviral therapy (ART) has saved millions of years of life [1], but it cannot eradicate latently infected cells [2,3]. The replication-competent provirus that remains during ART represents the major barrier to curing HIV [4]. Most of this latent reservoir resides in solid tissues and not in circulating blood, and we have yet to fully define the sanctuary sites of HIV persistence [5]. Timothy Ray Brown (known by many as the ‘Berlin Patient’) may be the closest to an HIV cure after being treated with an allogeneic hematopoietic stem cell transplant from a donor who was homozygous for the CCR5D32 deletion [6]. Unfortunately, this remarkable success has not been reproduced, and robust viral replication resumes almost universally following treat- ment interruption [7–9]. Even if strategies currently in development succeed in purging HIV from circulating CD4 þ T cells, residual virus can remain in the central nervous system (CNS), gut-associated lymphoid tissue (GALT), genital tract, adipose tissue, and others [9–12]. Thus, cure efforts must tackle the eradication of HIV reservoirs in anatomic compartments and sanctuaries throughout the body. The earliest stages of HIV infection are characterized by high levels of viral replication and little immune response [13,14]. This window of uncontrolled replication allows the virus to seed reservoirs throughout the body, as early as within 2 weeks of HIV infection [15], and to persist indefinitely throughout the lifespan of HIV-infected individuals [10]. These proviral reservoirs continue to expand and diversify until viral replication is successfully suppressed with ART. Despite extensive investigations, we still do not fully understand the dynamics of the total body HIV reservoir and how sub-reservoirs in various compart- ments relate to one another. For example, it remains unclear what factors govern the size and the activity of replication-competent HIV DNA in the CNS compared to the genital tract and blood. Most studies that have explored nonblood reservoirs among persons living with HIV infection have been limited to small samples of cerebrospinal fluid (CSF), genital secretion, gut, and shallow lymph nodes [10,16]. Studies using macaque models with simian immunodeficiency viruses (SIVs) have been enlightening for reservoirs in different tissues [17–23], but while SIV shares a high degree of structural and sequence identity to HIV, studies of SIV will not suffice to test eradication strategies for humans. For example, the Merck adenovirus type 5 (Ad5) trivalent HIV-1 vaccine trial (STEP trial) did not show efficacy in preventing HIV infection or slowing disease progression [24], despite promising results in various macaques’ trials [25–27]. As the field tackles the ambitious goal of eradicating HIV from the human body, we will need to test the effectiveness of cure interventions in living persons. a University of California, San Diego, La Jolla, b Community Advisory Board (CAB) AntiViral Research Center (AVRC), c Las Vegas, Nevada, and d Veterans Affairs San Diego Healthcare System, San Diego, California, USA. Correspondence to Sara Gianella, University of California San Diego, 9500 Gilman Drive, MC 0679, La Jolla, CA 92093-0679, USA. Tel: +1 858 642 1620; fax: +1 858 552 7445; e-mail: gianella@ucsd.edu Received: 18 August 2016; revised: 23 September 2016; accepted: 27 September 2016. DOI:10.1097/QAD.0000000000001300 ISSN 0269-9370 Copyright Q 2016 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Haplotypes and polymorphism in the CCR5 gene in sickle cell disease.

Sickle cell disease shows several clinical manifestations in distinct levels of severity. This heterogeneity is due to the haplotype variability associated with the HbS gene, levels of fetal hemoglobin and environmental conditions, which modify the disease expression. Science community believes that the presence of a polymorphism in the CCR5 gene, which is related to chronic inflammatory state, could confer a higher survival rate and a lower number of inflammatory events to these patients since the deletion in CCR5Δ32 would knock out the CCR5 gene. Therefore, this study aimed to identify the haplotypes in βS and βC genes, as well as to investigate the presence of the CCR5Δ32 deletion in patients with sickle cell disease. For this purpose, DNA was isolated with the QIAamp DNA Investigator Kit, and PCR was the method chosen to detect the mutant allele CCR5Δ32. The haplotypes in βS and βC genes were detected by RFLP with the restriction enzymes XmnI, HindIII, HincII, and HinfI analyzing six polymorphic sites on the β cluster, succeeded by electrophoresis. The atypical haplotype was the most common (54.3%), followed by Benin (28.6%), Bantu (11.5%), Senegal (2.8%), and Cameroon (2.8%). No patients presented CCR5Δ32 deletion. The increase in the frequency of atypical haplotypes suggests that these patients passed by variation in the genetic pattern from ancestral haplotypes throughout the years.

The Benefits of Early Antiretroviral Therapy for HIV Infection: How Early is Early Enough?

The case of the “Berlin Patient” is well-known. In 2007, an HIV-infected adult with leukemia underwent allogeneic hematopoietic stem cell transplant and was cured of his cancer (Hutter et al., 2009). As the donor was homozygous for the CCR5Δ32 deletion (which makes CD4+ T cells difficult to infect with HIV), the repopulated immune system lacked any detectable HIV and the patient has been apparently been cured. Two subsequent allogeneic transplants performed under potent ART (which protected the donor cells from de novo infection) resulted in a dramatic reduction in the frequency of cells harboring replication-competent HIV (generally referred to as the HIV “reservoir”) (Henrich et al., 2014). This was not enough to cure these two patients, however, as both individuals experienced a delayed but robust rebound in viremia after stopping therapy. A true cure will likely require complete eradication of the entire reservoir of HIV. This is a formidable challenge.

P21(WAF1/CIP1) RNA expression in highly HIV-1 exposed, uninfected individuals.

Some individuals remain HIV-1 antibody and PCR negative after repeated exposures to the virus, and are referred to as HIV-exposed seronegatives (HESN). However, the causes of resistance to HIV-1 infection in cases other than those with a homozygous CCR5Δ32 deletion are unclear. We hypothesized that human p21WAF1/CIP1 (a cyclin-dependent kinase inhibitor) could play a role in resistance to HIV-1 infection in HESN, as p21 expression has been associated with suppression of HIV-1 in elite controllers and reported to block HIV-1 integration in cell culture. We measured p21 RNA expression in PBMC from 40 HESN and 40 low exposure HIV-1 seroconverters (LESC) prior to their infection using a real-time PCR assay. Comparing the 20 HESN with the highest exposure risk (median = 111 partners/2.5 years prior to the 20 LESC with the lowest exposure risk (median = 1 partner/2.5 years prior), p21 expression trended higher in HESN in only one of two experiments (P = 0.11 vs. P = 0.80). Additionally, comparison of p21 expression in the top 40 HESN (median = 73 partners/year) and lowest 40 LESC (median = 2 partners/year) showed no difference between the groups (P = 0.84). There was a weak linear trend between risk of infection after exposure and increasing p21 gene expression (R2 = 0.02, P = 0.12), but again only in one experiment. Hence, if p21 expression contributes to the resistance to viral infection in HESN, it likely plays a minor role evident only in those with extremely high levels of exposure to HIV-1.

Genetic factors associated with slow progression of HIV among perinatally-infected Indian children.

To study the association between common AIDS restriction genes and slow disease progression among perinatally-infected children in India. ART-naïve children were identified and selected host factors including CCR5-∆32, SDF1-3'A, CCR5-59029G, HLA-B*27, B*57 were studied using allele-specific PCR-RFLP and SSPGo HLA typing kits. Among 165 children, 10 (6%) long-term non-progressors and 8 (5%) slow progressors were identified. For comparison, 12 children with normal progression of HIV were included. The frequencies of CCR5-∆32 deletion, SDF1-3'A and CCR5-59029G did not differ significantly. HLA-B*27 and B*57 were observed only in long-term non-progressors or slow progressors, who also harbored either SDF1-3'A and/or CCR5-59029G. There is an association between host genetic factors and slow disease progression in this population.

A variant of DC-SIGN gene promoter associated with resistance to HIV-1 in serodiscordant couples in Burkina Faso

ObjectiveTo study the involvement of variations in 4 genes associated with susceptibility and/or protection against HIV-1 in serodiscordant couples in Burkina Faso, namely, genes encoding HLA-B57, interferon regulatory factor 1 (IRF1), dendritic cell-specific ICAM3-grabbing nonintegrin (DC-SIGN) and CCR5 delta 32 (CCR5Δ32). MethodsTwo DC-SIGN and two IRF1 single nucleotide polymorphisms (SNPs) as well as HLA-B57*01 and CCR5Δ32 alleles were genotyped in 51 serodiscordant couples in Burkina Faso. DC-SIGN, IRF1 and HLA-B57*01 genotyping was carried out by real time PCR using TaqMan assays (Applied Biosystems, USA and Sacace Biotechnologies, Italy). CCR5Δ32 deletion was investigated by PCR. ResultsThe two SNPs of DC-SIGN promoter showed a significant genotypic difference in serodiscordant couples. After multivariate analysis, only the association between DC-SIGN rs2287886 and HIV-1 remained significant (P<0.01). No association was found between IRF1 SNPs and HIV-1 infection. CCR5Δ32 wild type allele was found in 100% of serodiscordant couples. A high frequency of HLA-B57*01 allele was found in the HIV-positive (78%) compared with HIV-negative group (51%), however this difference was no longer significant after the correction of the sex confounding effect in the logistic regression model. ConclusionsOur study suggests a protective role of a variation of DC-SIGN promoter and genetic resistance to HIV-1 in serodiscordant couples in Burkina Faso.

CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2

Background:Adoptive therapy with tumour-infiltrating lymphocytes (TILs) induces durable complete responses (CR) in ∼20% of patients with metastatic melanoma. The recruitment of T cells through CXCR3/CCR5 chemokine ligands is critical for immune-mediated rejection. We postulated that polymorphisms and/or expression of CXCR3/CCR5 in TILs and the expression of their ligands in tumour influence the migration of TILs to tumours and tumour regression.Methods:Tumour-infiltrating lymphocytes from 142 metastatic melanoma patients enrolled in adoptive therapy trials were genotyped for CXCR3 rs2280964 and CCR5-Δ32 deletion, which encodes a protein not expressed on the cell surface. Expression of CXCR3/CCR5 in TILs and CXCR3/CCR5 and ligand genes in 113 available parental tumours was also assessed. Tumour-infiltrating lymphocyte data were validated by flow cytometry (N=50).Results:The full gene expression/polymorphism model, which includes CXCR3 and CCR5 expression data, CCR5-Δ32 polymorphism data and their interaction, was significantly associated with both CR and overall response (OR; P=0.0009, and P=0.007, respectively). More in detail, the predicted underexpression of both CXCR3 and CCR5 according to gene expression and polymorphism data (protein prediction model, PPM) was associated with response to therapy (odds ratio=6.16 and 2.32, for CR and OR, respectively). Flow cytometric analysis confirmed the PPM. Coordinate upregulation of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumour biopsies was associated with OR.Conclusion:Coordinate overexpression of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumours was associated with responsiveness to treatment. Conversely, CCR5-Δ32 polymorphism and CXCR3/CCR5 underexpression influence downregulation of the corresponding receptors in TILs and were associated with likelihood and degree of response.

The 1000 Genomes Project: paving the way for personalized genomic medicine.

The 1000 Genomes Project: paving the way for personalized genomic medicine.

The chemokine receptorCCR5 Δ32allele in natalizumab-treated multiple sclerosis

The chemokine receptor CCR5 may be important for the recruitment of pathogenic T cells to the CNS in multiple sclerosis (MS). We hypothesized that this chemokine receptor might still be important for T-cell migration during treatment with anti-very late antigen (VLA)-4 antibody. We therefore analysed whether natalizumab-treated MS patients carrying the CCR5 Δ32 deletion allele, which results in reduced expression of CCR5 on the cell surface, had lower disease activity. CCR5 Δ32 was analysed in 212 natalizumab-treated MS patients. CCR5 Δ32 status had no significant impact on the frequency of relapses 1 year prior to natalizumab treatment or during the first 48 weeks of treatment. The multiple sclerosis severity score (MSSS) was significantly lower at baseline in patients carrying CCR5 Δ32 (P = 0.031). CCR5 Δ32 is not associated with lower disease activity in MS patients treated with natalizumab. We found lower MSSS scores in patients carrying CCR5 Δ32 compared with the remaining patients, which is consistent with previous studies reporting an association with a more favourable disease course. Further studies are, however, needed before the relationship between CCR5 Δ32 and disease activity in MS can be definitely established.

Association of Human Mannose Receptor in Sexual Transmission of Human Immunodeficiency Virus in Serodiscordant Couples

HIV binds specifically to the human mannose receptor (hMR) on vaginal epithelial cells that are devoid of a conventional CD4 receptor. HIV binding to hMR on vaginal epithelial cells induces the production of matrix metalloproteinase 9 (MMP9) leading to degradation of the extracellular matrix, which may increase the risk of HIV entry into vaginal epithelial cells and further transmission into distal cells. Immunofluorescent localization of hMR on vaginal epithelial cells of seronegative females from the general population included the control group (n=52) and seronegative females from serodiscordant couples. There was PCR amplification of DNA from peripheral blood mononuclear cells (PBMCs) of the serodiscordant females for the CCR5 gene flanking the CCR5-Δ32 region; PCR amplification and sequencing of the C2-V3 region of HIV variants in PBMCs and sperm of the infected male partners of the serodiscordant couples; and the presence of hMR on 0-11% of the vaginal epithelial cells of seronegative females (n=39) from serodiscordant couples and 90-95% that of a control group of females (n=52). Nine of these serodiscordant females did not show a CCR5-Δ32 deletion. The translated amino acid sequence of the C2-V3 region of the env gene of HIV-1C in PBMCs (n=9) and sperm (n=5) of the male partners showed the presence of distinct variants and the variation in PBMCs and sperm of serodiscordant males was almost similar to that of infected males from concordant couples. The presence of hMR in a smaller number of vaginal epithelial cells of serodiscordant females prevented binding and HIV entry into these cells and therefore prevented sexual transmission of HIV.