HLA Class I Binding of HBZ Determines Outcome in HTLV-1 Infection

CD8(+) T cells can exert both protective and harmful effects on the virus-infected host. However, there is no systematic method to identify the attributes of a protective CD8(+) T cell response. Here, we combine theory and experiment to identify and quantify the contribution of all HLA class I alleles to host protection against infection with a given pathogen. In 432 HTLV-1-infected individuals we show that individuals with HLA class I alleles that strongly bind the HTLV-1 protein HBZ had a lower proviral load and were more likely to be asymptomatic. We also show that in general, across all HTLV-1 proteins, CD8(+) T cell effectiveness is strongly determined by protein specificity and produce a ranked list of the proteins targeted by the most effective CD8(+) T cell response through to the least effective CD8(+) T cell response. We conclude that CD8(+) T cells play an important role in the control of HTLV-1 and that CD8(+) cells specific to HBZ, not the immunodominant protein Tax, are the most effective. We suggest that HBZ plays a central role in HTLV-1 persistence. This approach is applicable to all pathogens, even where data are sparse, to identify simultaneously the HLA Class I alleles and the epitopes responsible for a protective CD8(+) T cell response

Inhibition of Nipah Virus Infection In Vivo: Targeting an Early Stage of Paramyxovirus Fusion Activation during Viral Entry

In the paramyxovirus cell entry process, receptor binding triggers conformational changes in the fusion protein (F) leading to viral and cellular membrane fusion. Peptides derived from C-terminal heptad repeat (HRC) regions in F have been shown to inhibit fusion by preventing formation of the fusogenic six-helix bundle. We recently showed that the addition of a cholesterol group to HRC peptides active against Nipah virus targets these peptides to the membrane where fusion occurs, dramatically increasing their antiviral effect. In this work, we report that unlike the untagged HRC peptides, which bind to the postulated extended intermediate state bridging the viral and cell membranes, the cholesterol tagged HRC-derived peptides interact with F before the fusion peptide inserts into the target cell membrane, thus capturing an earlier stage in the F-activation process. Furthermore, we show that cholesterol tagging renders these peptides active in vivo: the cholesterol-tagged peptides cross the blood brain barrier, and effectively prevent and treat in an established animal model what would otherwise be fatal Nipah virus encephalitis. The in vivo efficacy of cholesterol-tagged peptides, and in particular their ability to penetrate the CNS, suggests that they are promising candidates for the prevention or therapy of infection by Nipah and other lethal paramyxoviruses

ANIMAL MODELS FOR THE STUDY OF LEISHMANIASIS IMMUNOLOGY

Leishmaniasis remains a major public health problem worldwide and is classified as Category I by the TDR/WHO, mainly due to the absence of control. Many experimental models like rodents, dogs and monkeys have been developed, each with specific features, in order to characterize the immune response to Leishmania species, but none reproduces the pathology observed in human disease. Conflicting data may arise in part because different parasite strains or species are being examined, different tissue targets (mice footpad, ear, or base of tail) are being infected, and different numbers (“low” 1×102 and “high” 1×106) of metacyclic promastigotes have been inoculated. Recently, new approaches have been proposed to provide more meaningful data regarding the host response and pathogenesis that parallels human disease. The use of sand fly saliva and low numbers of parasites in experimental infections has led to mimic natural transmission and find new molecules and immune mechanisms which should be considered when designing vaccines and control strategies. Moreover, the use of wild rodents as experimental models has been proposed as a good alternative for studying the host-pathogen relationships and for testing candidate vaccines. To date, using natural reservoirs to study Leishmania infection has been challenging because immunologic reagents for use in wild rodents are lacking. This review discusses the principal immunological findings against Leishmania infection in different animal models highlighting the importance of using experimental conditions similar to natural transmission and reservoir species as experimental models to study the immunopathology of the disease

An introduction to lymphocyte and viral dynamics: the power and limitations of mathematical analysis.

Mathematics is a useful tool in the analysis and understanding of population dynamic aspects of the immune response. However, the power of mathematical modelling in immunology is frequently limited by the shortage of experimental data. Here, we review the contribution of mathematics to two areas of immunology. We highlight the problem caused by lack of knowledge of the system, which can greatly restrict the use of mathematics and lead to errors caused by model-specific results

Mouse model to study the replication of primate foamy viruses.

A mouse model was developed to study the virus-host interaction of molecularly cloned human foamy virus (HFV) in vivo. The infectious process was analysed in two mouse strains, CBA/Ca and C57BL/6J, over a period of 24 weeks by PCR on DNAs from various animal tissues; virus serology was examined by immunoblotting. The infection persisted in both mouse strains and did not induce clinical symptoms. Upon infection of adult CBA/Ca mice HFV became detectable by PCR in an increasing number of organs over time. In contrast, in C57BL/6J mice, after an initial phase of dissemination, viral DNA sequences were found only in a few organs. Interestingly, the different course of infection was accompanied by differences in the antiviral immune response. In particular, C57BL/6J mice were high responders with respect to antibodies to the viral Bet protein, while CBA/Ca mice were low responders