Host genetic factors in susceptibility to HIV-1 infection and progression to AIDS

HIV-1 infection has rapidly spread worldwide and has become the leading cause of mortality in infectious diseases. The duration for development of AIDS (AIDS progression) is highly variable among HIV-1 infected individuals, ranging from 2–3 years to no signs of AIDS development in the entire lifetime. Several factors regulate the rate at which HIV-1 infection progresses to AIDS. Host genetic factors play an important role in the outcome of such complex or multifactor diseases as AIDS and are also known to regulate the rate of disease progression. This review focuses on the major host genes reported to affect the progression to AIDS in HIV-1 infected individuals.     

上海地区人类免疫缺陷病毒1型感染/艾滋病患者病毒耐药基因突变及亚型分布

目的 研究上海地区人类免疫缺陷病毒1型(HIV-1)感染／艾滋病(AIDS)患者中HIV-1耐药株出现的情况及亚型分布。方法 对33例HIV-1感染／AIDS患者的血浆HIV-1分离株,进行抗HIV-1药物(核苷类反转录酶抑制剂、非核苷类反转录酶抑制剂和蛋白酶抑制剂)的基因型耐药检测和亚型分析。结果 33例的HIV-1均未检出对PI的耐药突变;10例高效抗反转录病毒疗法(HAART)治疗失败或抑制病毒复制不完全者中,检出的耐药突变为70％,过渡型耐药突变为20％;23例未经抗HIV-1治疗者中,耐药突变为4．3％,过渡型耐药突变为13％。所有过渡型耐药突变均为T215S。15例经血制品传播的HIV- 1均为B亚型;18例经吸毒和性传播的HIV-1中,B和CRF01-AE亚型分别为39％,和33％,此外,还有C、D、G、K和CRF02-AG亚型。结论 上海地区HIV-1感染／AIDS患者中,HAART治疗失败或复制抑制不完全者HIV-1的NRTI和NNRTI耐药突变率高;吸毒和性传播者的HIV-1中,除主要为B和CRF01-AE亚型外,尚有其他少见的亚型。     

HIV-1 infection and AIDS: consequences for the central nervous system

Infection with the human immunodeficiency virus-1 (HIV-1) can induce severe and debilitating neurological problems that include behavioral abnormalities, motor dysfunction and frank dementia. After infiltrating peripheral immune competent cells, in particular macrophages, HIV-1 provokes a neuropathological response involving all cell types in the brain. HIV-1 also incites activation of chemokine receptors, inflammatory mediators, extracellular matrix-degrading enzymes and glutamate receptor-mediated excitotoxicity, all of which can trigger numerous downstream signaling pathways and disrupt neuronal and glial function. This review will discuss recently uncovered pathologic neuroimmune and degenerative mechanisms contributing to neuronal damage induced by HIV-1 and potential approaches for development of future therapeutic intervention.     

Virus phenotype switching and disease progression in HIV-1 infection

One of the phenotypic distinctions between different strains of human immunodeficiency virus type 1 (HIV-1) has to do with the ability to cause target cells to form large multinucleate bodies known as syncytia. There are two phenotypes according to this characterization: syncytium-inducing (SI) and non-syncytium-inducing (NSI). NSI strains are usually present throughout infection, while SI strains are typically seen at the beginning of the infection and near the onset of AIDS. The late emergence of SI strains is referred to as phenotype switching. In this paper we analyse the factors that lead to phenotype switching and contribute to the dynamics of disease progression. We show that a strong immune system selects for NSI strains while a weak immune system favours SI strains. The model explicitly accounts for the fact that CD4+ cells are both targets of HIV infection and crucial for activating immune responses against HIV In such a model, SI strains can emerge after a long and variable period of NSI dominated infection. Furthermore, versions of the model which do not explicitly account for HIV-specific, activated CD4+ cells do not exhibit phenotype switching, emphasizing the critical importance of this pool of cells.     

Chimeric synthetic peptide as antigen for immunodiagnosis of HIV-1 infection

One chimeric peptide incorporating antigenic sequences from the gp41 transmembrane region (peptide H-18) and the gp120 envelope region (peptide H-15) corresponding to amino acids (587-617) on gp41 and (495-516) on gp120 of human immunodeficiency virus (HIV 1) was synthesized. Both sequences were separated by two glycine residues. This peptide was evaluated as antigen in an ultramicro-enzyme-linked immunosorbent assay (UMELISA) with samples derived from HIV-1 (n = 30) with different titers of antibodies and healthy blood donors (n = 30). The results were compared to plates coated with monomeric peptides and to plates coated with two monomeric peptides together. Results demonstrated that monomeric peptides gp41 (H-18) and gp120 (H-15) were good as antigens with samples that present antibodies to these regions. The chimeric peptide was the most antigenic. Those results may be related to the peptide structure, adsorption to the solid surface, and epitope accessibility to the antibodies. This chimeric peptide would be very useful for HIV-1 diagnostics.     

B cell responses to HIV-1 infection and vaccination: pathways to preventing infection

The B cell arm of the immune response becomes activated soon after HIV-1 transmission, yet the initial antibody response does not control HIV-1 replication, and it takes months for neutralizing antibodies to develop against the autologous virus. Antibodies that can be broadly protective are made only in a minority of subjects and take years to develop--too late to affect the course of disease. New studies of the earliest stages of HIV-1 infection, new techniques to probe the human B cell repertoire, the modest degree of efficacy in a vaccine trial and new studies of human monoclonal antibodies that represent the types of immune responses an HIV-1 vaccine should induce are collectively illuminating paths that a successful HIV-1 vaccine might take.     

The association between HLA alleles (A, B, DRB1) and HIV-1 infection/ AIDS progression in the Han Chinese population of Hubei province

The association between HLA alleles (A, B, DRB1), haplotypes and AIDS progression in HIV-1 infected patients was investigated by analyzing and comparing the differences gene frequencies of HLA alleles (A, B, DRB1) and haplotypes in HIV-1 infected and AIDS individuals in Hubei province of China. Four hundred and twenty- four HIV-1 seropositive individuals were divided into two groups: HIV-1 infected group and AIDS patient group, according to diagnostic criteria. HLA-A, B, and DRB1 allele typing was performed using polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSOP) and polymerase chain reaction-sequencing based typing (PCR-SBT) techniques. Our study revealed that B*57:01 seemed resistant to AIDS progression, and the presence of DRB1*04:05 was associated with a poor disease outcome in HIV-1 infection. These associations were independent of age, sex, and transmission route of the host. No association was observed between HLA-A, B, DRB1 homozygotes, HLA-Bw4, Bw6 serological types and AIDS progression. We concluded that HLA gene polymorphism has a significant role in HIV-1 infection/AIDS progression. This observational study may open up avenues for precision medicine in the personalized prevention and treatment of AIDS.     

A novel strategy for inducing enhanced mucosal HIV-1 antibody responses in an anti-inflammatory environment

Prophylactic vaccination against HIV-1 sexual transmission will probably require antibody elicitation at genital mucosal surfaces. However, HIV-1 envelope glycoprotein (Env)-based antigens are weakly immunogenic, particularly when applied mucosally. The polyanion PRO 2000 is safe for human vaginal application, and thus may represent a potential formulating agent for vaginal delivery of experimental vaccine immunogens. Based upon its biochemical properties, we hypothesized that PRO 2000 might enhance mucosal immunogenicity of HIV-1 envelope glycoprotein (Env)-based antigens, promoting local and systemic immune responses. Vaginal immunization with Env-PRO 2000 resulted in significantly increased titres of Env-specific mucosal IgA and IgG in mice and rabbits, respectively, compared to Env alone, revealing modest but significant mucosal adjuvant activity for PRO 2000. In vitro, PRO 2000 associated with Env, protecting the glycoprotein from proteolytic degradation in human vaginal lavage. Unexpectedly, PRO 2000 antagonized TLR4 activation, suppressing local production of inflammatory cytokines. Since inflammation-mediated recruitment of viral target cells is a major risk factor in HIV-1 transmission, the immune modulatory and anti-inflammatory activities of PRO 2000 combined with its intravaginal safety profile suggests promise as an HIV-1 mucosal vaccine formulating agent.     

胰高血糖素样肽1:阿尔茨海默病治疗新策略

2型糖尿病(type2diabetes mellitus,T2DM)与阿尔茨海默病(Alzheimer’s disease,AD)的病理生理过程具有密切的相关性。人们正在逐步深入研究治疗T2DM的最新药物——胰高血糖素样肽1(glucagon-likepe ptide1,GLP-1)的神经保护作用,并大胆地提出了利用GLP-1治疗AD的设想。本文对T2DM与AD的发病相关性、GLP-1的合成与分泌、GLP-1受体的中枢分布及其生理效应,特别是GLP-1与AD治疗策略相关的研究进展作一综述。     

Blocking of the PD-1/PD-L1 interaction by a novel cyclic peptide inhibitor for cancer immunotherapy

The interaction of PD-1/PD-L1 allows tumor cells to escape from immune surveillance. Clinical success of the antibody drugs has proven that blockade of PD-1/PD-L1 pathway is a promising strategy for cancer immunotherapy. Here, we developed a cyclic peptide C8 by using Ph.D.-C7 C phage display technology. C8 showed high binding affinity with h PD-1 and could effectively interfere the interaction of PD-1/PD-L1. Furthermore, C8 could stimulate CD8+T cell activation in human peripheral blood mononuclear cells(PBMCs). We also observed that C8 could suppress tumor growth in CT26 and B16-OVA, as well as anti-PD-1 antibody resistant B16 mouse model. CD8+T cells infiltration significantly increased in tumor microenvironment, and IFN-γ secretion by CD8+T cells in draining lymph nodes also increased. Simultaneously, we exploited T cells depletion models and confirmed that C8 exerted anti-tumor effects via activating CD8+T cells dependent manner. The interaction model of C8 with h PD-1 was simulated and confirmed by alanine scanning. In conclusion, C8 shows anti-tumor capability by blockade of PD-1/PD-L1 interaction, and C8 may provide an alternative candidate for cancer immunotherapy.     

Advance in treatment strategy and immune reconstruction against HIV-1 infection

HIV-1 can be considered an infection of the immune system, resulting in progressive and ultimately profound immune suppression. The availability of highly active antiretroviral therapy (HAART) has resulted in dramatic changes in the disease course in persons fortunate enough to have access to these medications, but long-term therapy is limited by the development of resistance as well as toxicities of the potent medication regimens. Emerging data indicate that individuals who have non-progressive clinical course control HIV-1 immunologically. This has bolstered hope that the immune response might be effectively augmented in persons with HIV infection. Recent data indicating that immediate treatment of acute infection leads to augmentation of antiviral immune responses have provided evidence that the immune system might be enhanced in certain situations. Therefore, investigation in the reconstitution of anti-HIV immune response in patients under HAART should provide encouragement for continuing to explore methods to obtain meaningful and durable immune enhancement as an adjunct to HAART in HIV-1 infection.     

A novel cyclic opioid peptide analog showing high preference for mu-receptors

The side-chain to side-chain cyclized opioid peptide analogs H-Tyr-D-Orn-Phe-Asp-NH2 (I) and H-Tyr-D-Lys-Phe-Glu-NH2 (II) were synthesized and tested in the guinea pig ileum and mouse vas deferens assays and in binding assays based on displacement of mu- and delta-opioid receptor-selective radioligands from rat brain membranes. The more rigid cyclic analog I containing a 13-membered ring structure showed very high preference for mu-receptors over delta-receptors, whereas the more flexible cyclic peptide II (15-membered ring) was non-selective. These results indicate that variation in the degree of conformational restriction of opioid peptides can produce drastic shifts in their receptor selectivity profile. Because of its high mu-receptor selectivity and rigidity cyclic analog I will be useful for determining the conformational requirements of mu-opioid receptors.     

A novel cyclic octapeptide as an analogue of cyclic peptide in triostin A

This paper reported an ongoing study of cyclic peptides as carriers of potential anti-tumor agents. In an effort to carry out anti-cancer drug design, we synthesized another novel cyclic peptide as the analogue of the cyclic peptide in Triostin A. The linear peptide chains were synthesized by coupling protected amino acid residues according to Pfp/DCC methods (Pfp: Pentafluorophenol, DCC: N,N'-Dicyclohexyl-carbodiimide) in solution. After deblocking the Boc- group of the linear octapeptide chain, the cyclic product was achieved by employing diphenylphosphoryl azide (DPPA) as cyclic agent at low temperature in DMF. Further study on cyclic octapeptide-drug conjugates is in progress.     

Intranasal HIV-1-gp160-DNA/gp41 peptide prime-boost immunization regimen in mice results in long-term HIV-1 neutralizing humoral mucosal and systemic immunity

An intranasal DNA vaccine prime followed by a gp41 peptide booster immunization was compared with gp41 peptide and control immunizations. Serum HIV-1-specific IgG and IgA as well as IgA in feces and vaginal and lung secretions were detected after immunizations. Long-term humoral immunity was studied for up to 12 mo after the booster immunization by testing the presence of HIV-1 gp41- and CCR5-specific Abs and IgG/IgA-secreting B lymphocytes in spleen and regional lymph nodes in immunized mice. A long-term IgA-specific response in the intestines, vagina, and lungs was obtained in addition to a systemic immune response. Mice immunized only with gp41 peptides and L3 adjuvant developed a long-term gp41-specific serum IgG response systemically, although over a shorter period (1-9 mo), and long-term mucosal gp41-specific IgA immunity. HIV-1-neutralizing serum Abs were induced that were still present 12 mo after booster immunization. HIV-1 SF2-neutralizing fecal and lung IgA was detectable only in the DNA-primed mouse groups. Intranasal DNA prime followed by one peptide/L3 adjuvant booster immunization, but not a peptide prime followed by a DNA booster, was able to induce B cell memory and HIV-1-neutralizing Abs for at least half of a mouse's life span.     

HIV-1感染的共受体

早在1984年就已发现人免疫缺陷病毒一I型（HIV－l）感染细胞是通过与细胞表面受体CDe结合而进行的,但两年后又发现表达CDe的非人类细胞不能被IlfV－l感染,因此有人认为仅有CDe作为H］V－l的受体是不够的,还必须有人类细胞特异表达的某种辅助因子。最近,一些与CDe偶联的HIV则共受体已被陆续鉴定,它们均为趋化因子（chemokjnes受体家族的成员,也正是H］V－l感染所必需的辅助因子。互作为HIV—且共受体的趋化因子受体CXCR4是第一个被发现具有I］：IV－l共受体作用的蛋白质I’］,最初称为融合素（fusin）、LESTR等。最近…     

A novel strategy for the targeted analysis of protein and peptide metabolites

In many biological applications such as epitope discovery or drug metabolism studies, the detection of naturally processed exogenous proteins (e.g. vaccines or peptide therapeutics) and their metabolites is frequently complicated by the presence of a complex endogenous mixture of closely related or even identical compounds. We describe a method that incorporates stable isotope labelling of the protein of interest, allowing the selective screening of the intact molecule and all metabolites using a modified precursor ion scan. This method involves monitoring the low-molecular-weight fragment ions produced during MS/MS that distinguish isotopically labelled peptides from related endogenous compounds. All isotopically labelled peptides can be selected using this method. The technique makes no assumptions about the processed or post-translational state of the peptide, and hence can selectively screen out modified peptides that would otherwise be missed by single reaction monitoring approaches. This method does not replace single reaction monitoring or regular precursor scanning techniques; instead, it is a method that can be used when the assumptions required for the former two techniques cannot be predicted. The potential for this technique to be used in metabolism and pharmacokinetic experiments is discussed with specific examples looking at the metabolism of α-synuclein in serum and the brain.     

A unidirectional crosslinking strategy for HIV-1 protease dimerization inhibitors

A novel strategy to identify potent HIV-1 protease dimerization inhibitors was developed using 12-aminododecanoic acid as a tether to crosslink interfacial peptides. The directionality of the southern peptide was changed from N-->C to C-->N as compared to previously reported inhibitors. The terminal amine of the southern peptide and side chains were further diversified to find essential functional groups for dimerization inhibition of HIV-1 protease.     

A quantitative basis for antiretroviral therapy for HIV-1 infection

Highly active antiretroviral therapy (HAART) has dramatically decreased mortality from HIV-1 infection and is a major achievement of modern medicine. However, there is no fundamental theory of HAART. Elegant models describe the dynamics of viral replication, but a metric for the antiviral activity of drug combinations relative to a target value needed for control of replication is lacking. Treatment guidelines are based on empirical results of clinical trials in which other factors such as regimen tolerability also affect outcome. Why only certain drug combinations control viral replication remains unclear. Here we quantify the intrinsic antiviral activity of antiretroviral drug combinations. We show that most single antiretroviral drugs show previously unappreciated complex nonlinear pharmacodynamics that determine their inhibitory potential at clinical concentrations. We demonstrate that neither of the major theories for drug combinations accurately predicts the combined effects of multiple antiretrovirals. However, the combined effects can be understood with a new approach that considers the degree of independence of drug effects. This analysis allows a direct comparison of the inhibitory potential of different drug combinations under clinical concentrations, reconciles the results of clinical trials, defines a target level of inhibition associated with treatment success and provides a rational basis for treatment simplification and optimization.