MBL2 gene polymorphisms related to HIV-1 infection susceptibility and treatment response

Human Mannose-binding lectin (MBL) is a protein encoded by MBL2 gene involved in the activation of the lectin-complement pathway. Several studies emphasized the role of MBL2 gene in several infectious diseases’ susceptibility, including HIV-1 infection. We aim to investigate the impact of 10 MBL2 gene polymorphisms located in the promoter, 5′UTR and exon 1 regions on HIV-1 physiopathology. The polymorphisms genotyping of 400 individuals, which 200 were HIV-1 positive patients and 200 were controls, was performed by PCR-sequencing. Our results showed that rs503037 and rs1800451 polymorphisms are associated with a high risk of HIV-1 infection susceptibility while rs7096206 and rs11003123 showed a protective effect. A significant association between haplotype CGA and HIV-1 infection susceptibility was also found in the exon 1 region. Moreover, rs11003124, rs7084554, rs36014597 and rs11003123 polymorphisms revealed an association with treatment response outcome as measured by RNA viral load. This study highlights the importance of MBL2 polymorphisms in the modulation of HIV-1 infection susceptibility and the contribution to treatment response outcomes among Moroccan subjects.     

Cytokine and chemokine gene polymorphisms among ethnically diverse North Americans with HIV-1 infection

Twenty-four common single nucleotide polymorphisms (SNPs) in 10 cytokine and chemokine genes were defined in 579 North Americans at high risk of HIV-1 infection due to sexual behavior and injection drug use. Among the 3 major ethnic (African-American, Hispanic/Latino, and other) groups involved, HIV-1-seropositive individuals differed significantly from ethnically matched HIV-1-seronegative individuals (odds ratios = 2.13-4.82; P = 0.003-0.05) for several SNPs and haplotypes defined at the IL4, IL4R, IL6, IL10, CCL5 (RANTES), and CXCL12 (SDF1) loci. In addition, the homozygous IL4-590T/T genotype was associated with higher (+87-131 cells/microL) CD4 T-cell counts in HIV-1-infected and AIDS-free adolescents not receiving antiretroviral therapy (adjusted P = 0.004). No SNPs at IFNG, IL2, IL12B, TNF, or CCL2 (MCP1) showed any association with HIV-related outcomes. Additional typing for IL1A, IL1B, IL1R1, IL1RN, and TGFB1 SNPs also failed to demonstrate any influence on HIV-1 infection or virologic/immunologic control in more selected patient groups. Coupled with previous findings, our data suggest that heritable IL4 and IL10 variations may contribute to the acquisition or progression of HIV infection and that the effects of other targeted loci in the cytokine and chemokine system cannot be established unequivocally in the study populations.     

DC-SIGNR基因多态性与人类免疫缺陷病毒-1易感性的关联研究

目的 探索DC-SIGNR基因多态性对中国汉族人群人类免疫缺陷病毒-1(human immunodeficiency virus-1,HIV-1)病毒易感性的影响.方法 用聚合酶链反应、琼脂糖凝胶电泳结合测序对345例HIV-1血清阳性感染者及468例H1V-1血清阴性高危人群的DC-SIGNR基因绞链区重复序列分型,然后用卡方检验检测DC-SIGNR基因各亚型在不同人群组中出现的频率.结果 共发现DC-SIGNR基因14个基因型和5种等位基因,其中等位基因7出现的频率最高(67.1%),明显高于美国白人(67.1% vs.46.0%,P<0.01).HIV-1感染组7/7基因型的出现频率明显低于高危人群组(38.55% vs.48.29%,P=0.0057),而HIV-1感染组的9/5基因型的出现频率明显高于高危人群组(4.35% vs.1.07%,P=0.0029).结论 中国人群DC-SIGNR基因多态性分布有着独特的遗传学特征,中国人群中DC-SIGNR基因型9/5可能增加对HIV-1的易感性.     

HIV-1 integration: an interplay between HIV-1 integrase, cellular and viral proteins

To achieve a productive infection, the reverse transcribed cDNA of the human immunodeficiency virus type 1 (HIV-1) has to be inserted in the host cell genome. The main protein required to accomplish this reaction is the virally encoded integrase. In vitro, the recombinant integrase is capable of catalyzing the two subsequent reactions of the integration process, namely the 3' processing followed by the strand transfer, without other viral and/or cellular proteins. However, a number of studies indicate that the in vivo integration process also involves cellular proteins, assisting the virus to integrate in the cellular genome. These cellular proteins can play a role during different steps of the integration process, including nuclear import, integrase catalysis, integration site selection and DNA gap repair. In this review we summarize the candidate cellular proteins involved in the HIV-1 integration process identified so far and discuss their potential roles during HIV-1 replication.     

AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT): Rationale,Design, and Baseline Characteristics

Abstract

Purpose: This study assessed the utility of a placebo practice trial in determining adherence readiness among drug users. Method: Participants with histories of drug dependency completed a 2-week practice trial that mimicked HAART (Phase 1), followed by a 2-week observation of adherence to HAART (Phase 2) for those who began antiretroviral therapy during the study period. The primary measure of adherence was electronic monitoring. Results: There were 201 participants enrolled; 39% met criteria for current drug dependency. Mean adherence to the practice trial was 67%. Of the 184 Phase 1 completers, 83 (45%) initiated HAART prior to the end of the study. Mean adherence to HAART was 74%, including 33 patients (39%) with 90+% adherence. Adherence to the practice trial was correlated with antiretroviral adherence (r = .49, p < .001), and 90+% adherence to the practice trial was an accurate marker of the "adherence readiness" (ability to adhere 90+% on HAART) of 72% of the participants. In multivariate analyses, practice trial adherence was the best independent predictor of antiretroviral adherence, accounting for 19% of the explained variance; other predictors included adherence to recent clinic appointments, cognitive functioning, unstable housing, and adherence self-efficacy. Conclusion: These findings suggest that a brief placebo practice trial has the potential to provide clinicians and patients with an accurate screening tool for evaluating adherence readiness.     

Metabolic effects of protease inhibitor-sparing antiretroviral regimens given as initial treatment of HIV-1 Infection (AIDS Clinical Trials Group Study A5095)

OBJECTIVE: To assess metabolic changes after initiation of protease inhibitor (PI)-sparing regimens in antiretroviral-naive patients. METHODS: Metabolic changes were analyzed within the triple-nucleoside (zidovudine [ZDV]/lamivudine [3TC]/abacavir [ABC])-containing, 3-drug efavirenz (EFV) [ZDV/3TC + EFV]-containing, and 4-drug EFV [ZDV/3TC/ABC + EFV]-containing arms of the AIDS Clinical Trials Group multicenter trial A5095. Metabolic values were compared with published US general population norms. RESULTS: From week 0 to week 24, all arms exhibited similar mild median increases in glucose and decreases in insulin sensitivity, whereas changes in lipids were greater in the ZDV/3TC + EFV and ZDV/3TC/ABC + EFV arms than in the ZDV/3TC/ABC arm: triglyceride (TG; 7, 18, and -1 mg/dL, respectively), total cholesterol (TC; 23, 28, and 5 mg/dL, respectively), low-density lipoprotein cholesterol (LDL-C; 9, 14, and 1 mg/dL, respectively), and high-density lipoprotein cholesterol (HDL-C; 10, 10, and 5 mg/dL, respectively). Adjusted mean study lipid values of all study participants at week 0 and week 96 compared with those of the National Health and Nutrition Examination Survey (NHANES) 1999 through 2002 values were: TG (148, 187, and 123 mg/dL, respectively), TC (164, 195, and 203 mg/dL, respectively), HDL-C (35, 47, and 51 mg/dL, respectively), and LDL-C (101, 117, and 123 mg/dL, respectively) (P < or = 0.005 for each value vs. NHANES values). CONCLUSIONS: Similar mild increases in glucose and decreases in insulin sensitivity were observed in all regimens, whereas lipids were modestly higher in the EFV-containing arms. Compared with general population norms, the metabolic dysfunctions of concern after these PI-sparing therapies were increasingly abnormal TC and lower (but improved relative to baseline) HDL-C levels.     

Genetic determinants of HIV-1 infection and progression to AIDS: susceptibility to HIV infection

Interindividual variability in susceptibility to HIV-1 infection, its transmission, disease progression, and response to antiviral therapy has been attributed to host determinants and variability in multiple genes. Although most people exposed to the virus go on to develop full-blown disease at variable intervals, a proportion of them, labeled as long-term nonprogressors or exposed uninfected, possess 'natural resistance' to infection. A better understanding of genetic and immunologic basis of such a natural resistance to infection would bear important implications in designing therapeutic vaccine designs. The genetic variants that could influence susceptibility to HIV-1 and limit AIDS vary in different populations and among individuals. Meta-analyses of large cohort studies have identified numerous 'AIDS restriction genes' that regulate HIV cell entry (particularly chemokine coreceptors and their ligands), acquired and innate immunity (major histocompatibility complex, killer cell immunoglobulin-like receptor, and cytokines), and others [tripartite interaction motif 5 α (TRIM5α) and apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G] that influence outcome of HIV infection. Studies carried out in the Indian population with regard to genetic polymorphisms in chemokine receptors have shown that (i) the protective CCR5 Δ32 variant is rare, (ii) CCR5HHE carrying *59402A is associated with increased likelihood of infection and development of AIDS, and (iii) the Indian population generally has low CCL3L1 copy numbers (∼2.3). These data have implications in developing screening tests that could identify people at higher or lower risk of infection and rate of disease progression, predict vaccine responsiveness in clinical trials and understand the pathogenic mechanisms.     

MMP-7 promoter polymorphisms do not influence CD4+ recovery and changes in plasma viral load during antiretroviral therapy for HIV-1 infection

Matrix metalloproteinase-7 (MMP-7) generates soluble Fas Ligand (FasL), which is involved in the apoptotic loss of CD4+ T cells during HIV infection. We evaluated whether two polymorphisms in MMP-7 promoter could influence CD4+ recover in response to antiretroviral therapy, and found that these polymorphisms are ineffective.     

HIV-1 variability and progression to AIDS: a longitudinal study

HIV-1 replicative activity and its relation to the clinical and immunological evolution of infection was studied in a group of 150 HIV-1 seropositive Italian i.v. drug abusers over a 1 year period. HIV-1 was isolated from 90 (60%) subjects; two groups of isolates were distinguished, according to replicative activity "in vitro" and ability to induce cytopathic effects in cell cultures, and were termed "rapid-high" and "slow-low" viruses, in agreement with other workers. Rapid-high viruses were recovered more frequently from patients with ARC/AIDS, while slow-low viruses seemed related to the asymptomatic period of infection. The replicative properties of HIV-1 seem to affect strongly the course of disease. In fact, an important CD4 cell decline occurred in asymptomatic subjects with rapid-high virus infection; asymptomatic subjects with negative viral cultures or with slow-low viruses showed no such decline. Asymptomatic subjects with negative viral cultures had no signs of disease during the observation period, while 9% with slow-low virus and 45% with rapid-high virus progressed to AIDS.     

HIV-1 IgA specific serum antibodies and disease progression during HIV-1 infection

OBJECTIVE: To evaluate the role of serum human immunodeficiency virus type 1 immunoglobulin A (HIV-1 IgA) antibodies in the progression of HIV-1 infection in relation to viral load and CD4 cell counts. METHODS: Sequential serum specimens were obtained from 218 homosexual men: 123 HIV-1 seropositives, 24 HIV-1 seroconverters, and 71 HIV-1 seronegatives. HIV-1 IgA antibodies were tested blindly by enzyme-linked immunosorbent assay and Western blot. T-lymphocyte subsets were measured by flow cytometry. Viral plasma load was determined by a sensitive branched DNA assay. RESULTS: HIV-1 IgA antibodies with a titer greater than or equal to 50 were detected among 50% of the seroconverters, 27% of the HIV-1-seropositive asymptomatic subjects, 25% of lymphadenopathy, and 23% of HIV-1-related symptomatic subjects. Among patients with the acquired immune deficiency syndrome, the prevalence of virus-specific IgA antibodies (55%) was significantly higher (p < 0.03) as compared with the HIV-1-seropositive asymptomatic subjects, lymphadenopathy and HIV-1-related symptomatic patients, but not versus the seroconverters (p = 0.8). IgA antibodies to HIV-1 gP160 were the most prevalent among all subjects tested. A significant decrease in CD4 cell counts was observed after HIV-1 seroconversion. Viral load was slightly higher among the seroconverters who demonstrated higher (> or =50) HIV-1 IgA levels. CONCLUSIONS: HIV-1 IgA serum antibodies did not predict the progression of the disease. Correlation between HIV-1 IgA antibodies titer, viral load, and CD4 cell counts was not detected.     

Genetic determinants of HIV-1 infection and progression to AIDS: immune response genes

Genomic studies involving well-defined multicenter cohorts of HIV-1/AIDS covering multiple populations have led to a greater understanding of the role of host determinants in viral acquisition, disease progression, transmission, and response to anti-retroviral therapy. Similarly, recent knowledge on the virus genetic diversity has helped in elucidating mechanisms leading to the evolution of viral escape mutants and the role played by host immune determinants, in particular the major histocompatibility complex (MHC) associated genes. At least two alleles, HLA-B*27 and B*57, have been identified as 'protective' against HIV-1 while B*35 and B*53 act as susceptibility favoring factors. How human leukocyte antigen (HLA)-mediated selection drives the evolution of HIV-1 and which circulating variants are more likely to evade immune surveillance of the population are now beginning to become clear. Importantly, the rare HLA alleles in a population bear a selective advantage to the host because these can induce immune responses against pre-adapted viruses. It is conceivable that previously established protective HLA associations are shifting with the evolving cytotoxic T lymphocyte (CTL) epitopes and may not remain protective in future. At the same time, this process is unraveling novel sub-dominant epitopes of the virus which could now be incorporated as the dominant target CTL epitopes. An insight into the population-specific correlates of protection is hence necessary for designing future anti-HIV therapeutic and/or prophylactic vaccine formulation(s).     

SDF-1 gene polymorphisms and syncytia induction in Brazilian HIV-1 infected individuals

Stromal-derived factor (SDF-1) is the principal ligand for CXCR4, a co-receptor with CD4 for T lymphocyte cell line-tropic human immunodeficiency virus-type 1 (HIV-1). A common polymorphism, SDF1-3' A, was identified in an evolutionary conserved segment of the 3' untranslated region of the SDF-1 gene. Sequence analysis revealed a common variant at position 801, a G-->A transition referred to as SDF1-3' A. Because this variant eliminates the Msp I restriction site PCR-restriction fragment length polymorphism (RFLP) analysis was used for rapid detection of genotypes. We genotyped 62 HIV infected patients and 60 non-HIV blood donors by RFLP analysis. We also assessed syncytia formation through co-culture of MT-2 cells with peripheral blood mononuclear cells from HIV patients. Syncytium-inducing HIV-1 variants have been shown to be clinically significant in the pathogenesis of HIV-1 infection. In our study, we detected a low frequency of 3'A/3'A (5%) in the blood donors but this genotype was absent in all HIV patients. We found that 41 (68%) HIV patients including syncytia inducing (SI) and non-syncytia inducing (NSI) groups contained the wild type (wt/wt) genotype for SDF-1. Our data indicate that there is no correlation between SDF-1 alleles and syncytium inducing HIV.     

Links between progressive HIV-1 infection of humanized mice and viral neuropathogenesis

Few rodent models of human immunodeficiency virus type one (HIV-1) infection can reflect the course of viral infection in humans. To this end, we investigated the relationships between progressive HIV-1 infection, immune compromise, and neuroinflammatory responses in NOD/scid-IL-2Rγ(c)(null) mice reconstituted with human hematopoietic CD34(+) stem cells. Human blood-borne macrophages repopulated the meninges and perivascular spaces of chimeric animals. Viral infection in lymphoid tissue led to the accelerated entry of human cells into the brain, marked neuroinflammation, and HIV-1 replication in human mononuclear phagocytes. A meningitis and less commonly an encephalitis followed cM-T807 antibody-mediated CD8(+) cell depletion. We conclude that HIV-1-infected NOD/scid-IL-2Rγ(c)(null) humanized mice can, at least in part, recapitulate lentiviral neuropathobiology. This model of neuroAIDS reflects the virological, immunological, and early disease-associated neuropathological components of human disease.