Genetic Restriction Research Articles

Natural T cell immunity to intracellular pathogens and nonpeptidic immunoregulatory drugs.

Natural T (NT) lymphocytes recognize infected cells or microbial compounds without the classical genetic restriction of polymorphic major histocompatibility complex (MHC) molecules. This innate recognition pathway results in a broad and rapid antimicrobial response that may be critical for controlling the spread of intracellular pathogens, requiring the elimination of the infecting agent from both extracellular spaces and host cells. NT cells are mainly composed of alphabeta and gammadelta T lymphocytes that express natural killer (NK) receptors and recognize preferentially various nonpeptidic antigens. Similar to NK cells, NT lymphocytes can 'see' and kill target cells deficient in the expression of one or more MHC class I molecules. NT cells expressing the alphabeta TCR can recognize lipid and lipoglycan antigens presented in the context of nonpolymorphic CD1 molecules, whereas phosphocarbohydrates and akilamines induce constitutive responses in most Vgamma9Vdelta2 NT lymphocytes. The remaining fraction of gammadelta NT cells express the Vdelta1 chain associated with different Vgamma-chains and may directly recognize self-antigens such as MICA, MICB or CD1 molecules. It is possible that NT lymphocytes may play two opposite roles during intracellular infections. First, in the acute phase, they may be critical for the initiation of pathogen elimination. Second, in the chronic phase, NT cells may be dangerous, if their potential autoreactivity is not well controlled. It is conceivable that novel strategies of immune intervention against emerging and re-emerging intracellular pathogens, such as human immundeficiency virus (HIV), hepatitis-C virus (HCV) and Mycobacterium tuberculosis (MTB) may involve the control of NT cell activation/anergy by (nonpeptidic) immunoregulatory drugs.

Genetic restriction of HIV-1 pathogenesis to AIDS by promoter alleles of IL10.

IL10 is a powerful TH-2 cell cytokine produced by lymphoid cells that limits HIV-1 replication in vivo, ostensibly by inhibiting macrophage/monocyte and T-cell lymphocyte replication and secretion of inflammatory cytokines (IL1, TNFalpha, IL6, IL8, and IL12). A genetic epidemiological scan of patients enrolled in AIDS cohorts for candidate gene-linked short tandem repeat polymorphisms revealed significant genotype associations for HIV-1 infection and progression to AIDS with markers adjacent to and tracking (by linkage disequilibrium) common single nucleotide polymorphic variants in the IL10 promoter region. Individuals carrying the IL10-5'-592A (IL10-5'A) promoter allele possibly were at increased risk for HIV-1 infection, and once infected they progressed to AIDS more rapidly than homozygotes for the alternative IL10-5'-592 C/C (IL10-+/+) genotype, particularly in the later stages of HIV-1 infection. An estimated 25-30% of long-term nonprogressors (who avoid clinical AIDS for 10 or more years after HIV-1 infection) can be attributed to their IL10-+/+ promoter genotype. Alternative IL10 promoter alleles are functionally distinct in relative IL10 production, in retention of an avian erythroblastosis virus transcription factor recognition sequence and in binding to specific putative nuclear transcription factors, suggesting a potential mechanism whereby IL10-5'A down-regulation of inhibitory IL10 facilitates HIV-1 replication in vivo, accelerating the onset of AIDS.

Inducing protective antibodies against ring-infected erythrocyte surface peptide antigen of Plasmodium falciparum using immunostimulating complex (ISCOMs) delivery.

In the present study, synthetic peptides (EENVEHDA)2 [(oc)2] and (DDEHVEEPTVA)2 [(un)2] of ring-infected erythrocyte surface antigen (RESA) of Plasmodlium filciparum were linked with palmitic acid and entrapped in immunostimulating complexes (ISCOMs). The immunogenicity of the peptide(s) and mixture of peptides were studied in mice with different genetic background. Peptide(s) entrapped in ISCOMs using a low-dose immunization strategy generated high-titer as well as high-affinity antibodies. Interestingly, no genetic restriction of the immune response was observed in any of the strains studied. The IgG subclass pattern with the peptide(s) showed predominately IgG2a/2b isotypes, while with the mixed peptide formulation, (un)2-specific IgG isotype pattern showed induction of both IgG1 and IgG2a/2b isotypes. These cytophilic antibodies inhibited the ring as well as schizont stage and total parasite growth during in vitro merozoite reinvasion inhibition study. In the mixed peptide preparation, the same pattern of immune response was achieved as that of individual peptide(s) using ISCOMs delivery. Therefore, the entrapment of otherwise poorly immunogenic synthetic peptides in ISCOMs resulted in increased immunogenicity followed by strong secondary response and can be adopted for developing subunit immunogen formulation against malarial parasite.

Genetic use restriction technologies and the diffusion of yield gains to developing countries

AbstractThe focus of this paper is the analysis of genetic use restriction technologies (GURTs) from the perspective of the diffusion of crop improvements to developing countries. One of the possible consequences of genetic use restriction technologies is a distinct downward shift in the growth trajectories of agricultural productivity in developing countries by restricting the flow of innovations to which these countries have had access in the past. In this case, developing countries are likely to face cumulative losses in agricultural productivity growth as a result of widespread adoption of GURTs by crop innovators. This paper presents the results of a study on hybrid crops, a precursor technology, to establish the negative effect of use restriction technologies on diffusion and discusses the implications of widespread use of GURTs for developing countries. Copyright © 2000 John Wiley & Sons, Ltd.

Molecular epidemiological survey of Listeria monocytogenes in seafoods and seafood-processing plants.

To evaluate the role of seafoods in the epidemiology of human listeriosis and the role of the processing environment as a source of Listeria monocytogenes in seafood products, 305 L. monocytogenes isolates were characterized by multilocus enzyme electrophoresis using 21 genetic loci and restriction enzyme analysis of total DNA. Forty-four isolates were recovered from patients in Norway; 93 were isolated from seafoods, seafood-processing environments, and seawater from 55 different producers; and the remaining 168 isolates originated from six seafood-processing plants and one transport terminal examined in detail for L. monocytogenes. The patient isolates fell into 11 electrophoretic types, with four of them being responsible for 77% of the listeriosis cases in 1992 to 1996. Isolates from Norwegian seafoods and processing environments showed great genetic diversity, indicating that seafoods and seafood-processing environments do not offer a niche for specific L. monocytogenes strains. On the other hand, isolates from individual processing plants were genetically more homogenous, showing that plants are likely to be colonized with specific subclones of L. monocytogenes. The isolation of identical subclones of L. monocytogenes from both human patients and seafoods, including ready-to-eat products, suggests that such products may have been possible sources for listeriosis cases in Norway.

Fine-Scale Comparative Mapping of the Human 7q11.23 Region and the Orthologous Region on Mouse Chromosome 5G: The Low-Copy Repeats That Flank the Williams–Beuren Syndrome Deletion Arose at Breakpoint Sites of an Evolutionary Inversion(s)

Williams–Beuren syndrome (WBS) is a developmental disorder caused by haploinsufficiency for genes deleted in chromosome band 7q11.23. A common deletion including at least 16–17 genes has been defined in the great majority of patients. We have completed a physical and transcription map of the WBS region based on analysis of high-throughput genome sequence data and assembly of a BAC/PAC/YAC contig, including the characterization of large blocks of gene-containing low-copy-number repeat elements that flank the commonly deleted interval. The WBS deletions arise as a consequence of unequal crossing over between these highly homologous sequences, which confer susceptibility to local chromosome rearrangements. We have also completed a clone contig, genetic, and long-range restriction map of the mouse homologous region, including the orthologues of all identified genes in the human map. The order of the intradeletion genes appears to be conserved in mouse, and no low-copy-number repeats are found in the region. However, the deletion region is inverted relative to the human map, exactly at the flanking regions. Thus, we have identified an evolutionary inversion with chromosomal breakpoints at the sites where the human 7q11.23 low-copy-number repeats are located. Additional comparative mapping suggests a model for human chromosome 7 evolution due to serial inversions leading to genomic duplications. This high-resolution mouse map provides the framework required for the generation of mouse models for WBS mimicking the human molecular defect.

Research note: HLA degenerate T-cell epitopes from Plasmodium falciparum liver stage-specific antigen 1 (LSA-1) are highly conserved in isolates from geographically distinct areas.

Considerable effort is directed at the development of a malaria vaccine that elicits antigen-specific T-cell responses against pre-erythrocytic antigens of Plasmodium falciparum. Genetic restriction of host T-cell responses and polymorphism of target epitopes on parasite antigens pose obstacles to the development of such a vaccine. Liver stage-specific antigen-1 (LSA-1) is a prime candidate vaccine antigen and five T-cell epitopes that are degenerately restricted by HLA molecules common in most populations have been identified on LSA-1. To define the extent of polymorphism within these T-cell epitopes, the N-terminal non-repetitive region of the LSA-1 gene from Malaysian P. falciparum field isolates was sequenced and compared with data of isolates from Brazil, Kenya and Papua New Guinea. Three of the T-cell epitopes were completely conserved while the remaining two were highly conserved in the isolates examined. Our findings underscore the potential of including these HLA-degenerate T-cell epitopes of LSA-1 in a subunit vaccine.

Genetic restriction of Plasmodium falciparum in an area of stable transmission: an example of island evolution?

To date, a high degree of polymorphism has been demonstrated at both the MSP1 and MSP2 loci in parasites from areas of stable malaria transmission. As a consequence, in such areas it is rare to find parasites of the same 2-locus genotype in more than 1 subject. We have studied MSP1 and MSP2 diversity in parasites collected from subjects with both symptomatic (n = 86) and asymptomatic (34) malaria living on the island of Santo, Vanuatu, an area of stable malaria transmission. Polymorphism at the MSP1 and MSP2 loci was considerably less than previously reported: only 5 MSP1 and 5 MSP2 alleles were detected and these showed no size variation within alleles. Santo is unique amongst the areas studied so far in that it is a small island at the limit of the malaria belt in the South Pacific. Thus, the evolution of the parasite population may have been affected by the small size and isolation of this island population. Moreover, limited parasite diversity may explain the unusually mild nature of Plasmodium falciparum disease on Santo. Islands have fascinated biologists for centuries and fuelled the advancement of evolutionary theory, since they are natural laboratories for the study of evolution. The simplicity of the Vanuatu P. falciparum population may facilitate the use and interpretation of sequence level analyses to address the mechanisms by which genetic diversity is generated and maintained in natural populations.

Genetic restrictions in olive pollen allergy

Background: The major antigen of olive tree pollen, Ole e 1, produces an IgE response restricted by DQ2. Objective: Our purpose was to further analyze the genetic restrictions associated with IgE and IgG antibodies against Ole e 1 and IgE against the recently described antigen Ole e 3. Methods: Twenty-two nuclear olive pollen–allergic families (n = 88) were selected. DRB1 and DQB1, TCR-Vα 8.1, the high-affinity receptor of IgE (FcϵRI-β) Rsa I exon 7 and intron 2 and TNF-β (LTα–Nco I) polymorphisms were determined by PCR and analyzed for association with allergic traits by the multiallelic transmission disequilibrium test. Results: Significant associations were found among HLA-DQB1*0201 (n = 29) and high levels of IgG (P = .023) and IgE (P = .0136) antibodies to Ole e 1 and with IgE specific to Ole e 3 (P = .0368). DRB1*0701 was associated with high levels of total serum IgE (P = .04) and IgG against Ole e 1 (P = .025). The FcϵRI-β Rsa I exon 7, allele 1 (n = 39), was associated with high levels of total serum IgE (P = .01), IgE antibodies against Olea europaea extract (P = .004), and specific antibodies to Ole e 1, IgG (P = .04), and IgE (P = .006). The FcϵRI-β Rsa I intron 2, allele 2 (n = 33), was associated with IgE antibodies to O europaea extract (P = .003) and specific antibodies to Ole e 1, IgG (P = .025), and IgE (P = .05). Conclusions: We found a new association between IgE antibody response to Ole e 3 and DQB1*0201 and verified the previously reported association between Ole e 1–specific response and DQB1*0201. Also, the association between FcϵRI-β and IgE antibodies against Ole e 1 was demonstrated. (J Allergy Clin Immunol 2000;105:292-8.)

GENÉTICA DA ASSOCIAÇÃO DE INSETOS COM PLANTAS HOSPEDEIRAS

We present here the theoretical principles and main genetic methodologies for the study of speciation in insect herbivores. The presence of genetic polymorphism in herbivore populations may be associated to ecological factors, like the chemical variability in host plants. In this sense, we study the genetic-ecological relations like oviposition preference and larval performance, use of life tables of herbivore placed over different host plants, and mainly the geographic variation of characters associated to host plant exploitation. The use of the concept of host-race, or, herbivore populations that present specializations to a certain host plants, adds, to the study of crypyic species. We search the existence of these species when we find, in the same locus , different alleles fixed in different sympatric species host-races. We believe that host shifts were the prevalent events in the sympatric differentiation of herbivores, and that these would be associated to shifts in the polymorph characters associated to host exploitation. It is suggested that host shifts are associated to ecological and genetic restrictions. It is accepted that the great diversity of plant secondary chemicals evolved as a response to the attack of insect herbivores and that some insects evolved in response to the changes in their host plants, so, resulting from a diffuse coevolution between plants and herbivores. A similar process seeks to explain the patterns of herbivore and plant diversification, namely, “escape and radiation coevolution”. Finally, the analysis of phylogenies may provide evidence, based on the patterns of diversification of herbivores and their host plants, for the functions played by genetics, physiology, ecology, and geography in the evolution of these groups.

Vaccine adverse events in the new millennium: is there reason for concern?

As more and more infectious agents become targets for immunization programmes, the spectrum of adverse events linked to vaccines has been widening. Although some of these links are tenuous, relatively little is known about the immunopathogenesis of even the best characterized vaccine-associated adverse events (VAAEs). The range of possible use of active immunization is rapidly expanding to include vaccines against infectious diseases that require cellular responses to provide protection (e.g. tuberculosis, herpes viral infections), therapeutic vaccines for chronic infections (e.g. human immunodeficiency virus (HIV) infection, viral hepatitis B and C), and vaccines against non-infectious conditions (e.g. cancer, autoimmune diseases). Less virulent pathogens (e.g. varicella, rotavirus in the developed world) are also beginning to be targeted, and vaccine use is being justified in terms of societal and parental "costs" rather than in straightforward morbidity and mortality costs. In the developed world the paediatric immunization schedule is becoming crowded, with pressure to administer increasing numbers of antigens simultaneously in ever simpler forms (e.g. subcomponent, peptide, and DNA vaccines). This trend, while attractive in many ways, brings hypothetical risks (e.g. genetic restriction, narrowed shield of protection, and loss of randomness), which will need to be evaluated and monitored. The available epidemiological and laboratory tools to address the issues outlined above are somewhat limited. As immunological and genetic tools improve in the years ahead, it is likely that we shall be able to explain the immunopathogenesis of many VAAEs and perhaps even anticipate and avoid some of them. However, this will only happen if the human and financial resources needed for monitoring and studying vaccine safety stay in step with the accelerating pace of vaccine development. Failure to make such a commitment would put all immunization programmes at risk.

Genetic Use Restriction Technologies (GURTs): impacts on developing countries

This paper sets out the potential impacts of GURTs on various developing countries. The impact on any country depends on a number of important factors existing biotechnology capability, capacity for developing biotechnology, and the country's suitability for planting non-hybridised modern varieties. For a large group of developing countries the potential impact from GURTs will be dependent on the impact of these technologies on the rate of diffusion of innovation from countries that possess biotechnological capabilities to those countries that do not. This is necessarily an empirical question, because there are two important effects that are countervailing the impact of GURTs on the general rate of innovation and the impact of GURTs on the rate of diffusion between countries. To address this question, a case study is constructed assessing the impact of hybridised varieties on the diffusion of innovation within maize production. This case study indicates that hybridisation as a URT has slowed the overall rate of diffusion of innovation to many developing countries. When GURTs are introduced it will be important to increase public spending for diffusion of innovations to continue.

Definition of the stage of host cell genetic restriction of replication of human immunodeficiency virus type 1 in monocytes and monocyte-derived macrophages by using twins.

Using identical (ID) twins, we have previously demonstrated that host cell genes exert a significant impact on productive human immunodeficiency virus (HIV) infection of monocytes and macrophages (J. Chang et al., J. Virol. 70:7792-7803, 1996). Therefore, the stage in the replication cycle at which these host genetic influences act was investigated in a study using 8 pairs of ID twins and 10 pairs of sex- and age-matched unrelated donors (URDs). In the first phase of the study, blood monocytes and monocyte-derived macrophages (MDM) of ID twins and URDs were infected with 15 HIV type 1 strains. Four well-characterized primary isolates and HIV-BaL were then examined in more detail. The host cell genetic effect in MDM was exerted predominantly prior to complete reverse transcription, as the HIV DNA level and p24 antigen levels were concordant (r = 0.91, P = 0.0001) and similar between the pairs of ID twin pairs (r = 0.96, P = 0.0001) but discordant between URD pairs (r = 0.11, P = 0.3) in both phases of the study. To further examine genetic influence on viral entry, we examined the proportion of CCR5 membrane expression on MDM. As expected, there was wide variability in proportion of MDM expressing CCR5 among URDs (r = 0. 58, P = 0.2); however, this variability was significantly reduced between ID twin pairs (r = 0.81, P = 0.01). Differences in viral entry did not necessarily correlate with CCR5 expression, and only very low levels of CCR5 expression restricted HIV entry and production. In summary, the host cell genetic effect on HIV replication in macrophages appears to be exerted predominantly pre-reverse transcription. Although CCR5 was necessary for infection, other unidentified host genes are likely to limit productive infection.

In vivo Priming of TNP-reactive Effector Cells in Carp.

In a study of immune mechanisms in fish, specific cell-mediated cytotoxic activity against trinitrophenyl (TNP) -modified autologous peripheral blood leucocytes (PBL) was successfully induced in in vivo primed carpCyprinus carpio. The cytotoxic activity increased in proportion to the number of immunizations. The cytotoxic activity was shown to be gradually reduced with time afterin vivosensitization, and was finally lost. In addition, cytotoxic activities against TNP-modified allogeneic PBLs (T-ALLO-PBL) in carp immunized with TNP-modified autologous PBLs (T-AUTO-PBL) were not detected and effector cells from carp immunized with T-ALLO-PBL were not significantly cytotoxic against T-AUTO-PBL. Thus, the occurrence of a genetic restriction in carp was shown using thein vivopriming model. These results suggest that specific cell-mediated cytotoxicity ofin vivoprimed carp in some respects resembles mammalian cytotoxic T cells.

Simultaneous induction of multiple antigen-specific cytotoxic T lymphocytes in nonhuman primates by immunization with a mixture of four Plasmodium falciparum DNA plasmids.

CD8(+) T cells have been implicated as critical effector cells in protective immunity against malaria parasites developing within hepatocytes. A vaccine that protects against malaria by inducing CD8(+) T cells will probably have to include multiple epitopes on the same protein or different proteins, because of parasite polymorphism and genetic restriction of T-cell responses. To determine if CD8(+) T-cell responses against multiple P. falciparum proteins can be induced in primates by immunization with plasmid DNA, rhesus monkeys were immunized intramuscularly with a mixture of DNA plasmids encoding four P. falciparum proteins or with individual plasmids. All six monkeys immunized with PfCSP DNA, seven of nine immunized with PfSSP2 DNA, and five of six immunized with PfExp-1 or PfLSA-1 DNA had detectable antigen-specific cytotoxic T lymphocytes (CTL) after in vitro restimulation of peripheral blood mononuclear cells. CTL activity was genetically restricted and dependent on CD8(+) T cells. By providing the first evidence for primates that immunization with a mixture of DNA plasmids induces CD8(+) T-cell responses against all the components of the mixture, these studies provide the foundation for multigene immunization of humans.

Schistosoma mansoni:Genetic Restriction and Cytokine Profile of the CD4 + T Helper Cell Response to Dominant Epitope Peptide of Major Egg Antigen Sm-p40

Hernandez, H. J., Edson, C. M., Harn, D. A., Ianelli, C. J., and Stadecker, M. J. 1998.Schistosoma mansoni: Genetic restriction and cytokine profile of the CD4+ T helper cell response to dominant epitope peptide of major egg antigen Sm-p40.Experimental Parasitology90, 122–130. Granuloma formation in schistosomiasis is mediated by MHC class II-restricted CD4 + T helper lymphocytes sensitized to egg antigens. We previously reported that C3H mice, which develop large granulomas, display strong CD4 + T helper cell responses to the major egg antigen Sm-p40. Moreover, all members of a panel of egg antigen-specific T cell hybridomas responded to the Sm-p40 antigen. Given the significance of the Sm-p40 molecule in the C3H T cell repertoire against schistosomal egg antigens, the current work was undertaken to map its immunogenic epitopes, using a library of 15 synthetic overlapping 30-mer peptides. The dominant epitope recognized by polyclonal CD4 + Th cells was located in peptide 10 (amino acids 229–258); subdominant epitopes were detected in peptides 8 (amino acids 179–208) and 12 (amino acids 279–308). The anti-Sm-p40 T cell hybridomas variously responded to any one of the same three stimulatory peptides. Furthermore, studies with various mouse strains demonstrated that a strong anti-Sm-p40 response was restricted by H-2k. Interestingly, the cells responding to peptide 10 and to the Sm-p40 antigen only secreted IL-2 and IFN-γ, but not IL-4 and IL-10, indicating that they are entirely of the Th-1-type, a subset with demonstrated capacity to mediate egg granuloma formation. The identification of dominant epitopes within key egg antigens offers opportunities for desensitization of the CD4 + Th cells that mediate pathology in schistosomia sis.

CD4(+) T cell and natural killer cell-dependent killing of Mycobacterium tuberculosis by human monocytes.

We established an in vitro model of the phagocytosis of Mycobacterium tuberculosis by human peripheral blood monocytes to evaluate the subsequent inhibition of intracellular replication of the organism. Highly purified T cells (94% CD3(+)/CD16(-)) or natural killer (NK) cells (96% CD16(+)/CD3(-)) isolated by Percoll discontinuous density gradient of peripheral blood mononuclear cells were incubated with M. tuberculosis-infected monocyte monolayers. Monocytes were lysed immediately and at 4, 7, and 10 d after infection for quantification of intracellular replication, which was assessed by quantitative plating techniques as colony-forming units (CFU). Whereas control monocytes permitted intracellular replication, T cells activated monocytes to kill 77% (p < 0.01) of intracellular M. tuberculosis compared with control monocytes by 10 d after infection. NK cells activated monocytes to kill 84% (p < 0.01) of M. tuberculosis in comparison with control monocytes. Lymphokine (IL-2)-activated-killer (LAK) cells were capable of activating monocytes to kill 97% (p < 0.01) of the intracellular organisms compared with control monocytes. In purified protein derivative (PPD)-positive donors, PPD-specific-CD4(+) lymphocytes stimulated monocytes to kill intracellular M. tuberculosis in a Class II major histocompatibility complex-restricted manner. In contrast, in PPD-negative donors, CD4(-) lymphocytes activated monocytes in a genetically unrestricted manner. Both T cell supernatant and NK cell supernatant generated from cocultivation with M. tuberculosis-infected monocytes also activated monocytes to augment mycobactericidal function. In conclusion, T cells, NK cells, LAK cells, and their supernatants activated mycobactericidal function of monocytes, although these pathways of activation differed in terms of antigenic specificity and genetic restriction.

Evidence for epitope-specific thymus-independent response against a repeat sequence in a protein antigen.

We have studied the immunogenicity of a recombinant heat-shock protein-related stress protein of 70,000 MW (Pfhsp) of the human malaria parasite Plasmodium falciparum in H-2 congenic and non-congenic strains of inbred and outbred mice. Most mice of different genetic backgrounds produced antibodies to Pfhsp, indicating a lack of any apparent genetic restriction of immune response. A peptide corresponding to the GGMP repeat sequence in the C-terminal region of Pfhsp was recognized by more than 75% of sera from immunized mice. The GGMP repeat epitope-specific antibodies were largely of the IgM isotype, especially in all seven inbred strains of mice tested. The lack of significant boosting of the immune response, a predominantly IgM isotype of antibodies and generation of antibody responses in athymic nude mice suggest a thymus-independent response against the GGMP repeat epitope in the Pfhsp molecule.

Protective effect of an SDF-1 variant in HIV disease: abstract and commentary.

Stromal-derived factor (SDF-1) is the principal ligand for CXCR4, a coreceptor 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 evolutionarily conserved segment of the 3′ untranslated region of the SDF-1 structural gene transcript. In the homozygous state, SDF1-3′A/3′A delays the onset of acquired immunodeficiency syndrome (AIDS), according to a genetic association analysis of 2857 patients enrolled in five AIDS cohort studies. The recessive protective effect of SDF1-3′A was increasingly pronounced in individuals infected with HIV-1 for longer periods, was twice as strong as the dominant genetic restriction of AIDS conferred by CCR5 and CCR2 chemokine receptor variants in these populations, and was complementary with these mutations in delaying the onset of AIDS.

Plasmodium falciparum polyoximes: highly immunogenic synthetic vaccines constructed by chemoselective ligation of repeat B-cell epitopes and a universal T-cell epitope of CS protein

Effective immunoprophylaxis directed against the pre-erythrocytic stages of the malaria parasite requires a vaccine that can elicit humoral and cell mediated immunity in individuals of diverse genetic background. In order for a synthetic peptide malaria vaccine to meet these requirements, problems associated with genetic restriction, peptide chemistry, adjuvant formulation and physiochemical characterization of the final synthetic vaccine product must first be overcome. To address these issues, five polyoxime vaccine candidates have been constructed by ligating purified peptide epitopes of the P. falciparum CS protein to a branched template via oxime bonds. All five constructs, including two based on templates containing the synthetic adjuvant tripalmitoyl-S-glyceryl cysteine (Pam3Cys), were of sufficient purity for characterization by mass spectrometry. The immunogenicity of the malaria polyoximes in different murine strains was compared to that of multiple antigen peptide (MAP) constructs synthesized by standard step-wise synthesis. A tri-epitope polyoxime-Pam3Cys construct, based on the repeats and a universal T-cell epitope that contains both helper and CTL epitopes of the CS protein, was shown to be a precisely-defined synthetic malaria vaccine candidate that was highly immunogenic in murine strains of diverse H-2 haplotypes.