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PathCO Report Summary

Project ID: 305578
Funded under: FP7-HEALTH
Country: United Kingdom

Periodic Report Summary 3 - PATHCO (Pathogen COinfection:HIV, Tuberculosis, Malaria and Hepatitis C virus)

Project Context and Objectives:
Acquired immune deficiency (AIDS), tuberculosis (TB) and malaria are the primary infectious diseases causing death world-wide. In addition to these pathogens, 170 million people are infected with hepatitis C virus (HCV), which leads to chronic liver disease. Because of shared routes of transmission, HCV co-infection is recognized as a major cause of morbidity and mortality among HIV-1 infected persons. The epidemiology and clinical features of co-infected subjects are well documented, however, there is a paucity of basic scientific studies addressing the interactions between these pathogens. There is undoubtedly a complex interplay between pathogens and the host immune response. This was highlighted when the Merck HIV-1 vaccine trial was halted due to increased HIV-1 transmission amongst vaccine recipients with previous adenovirus infection, suggesting that immune responses specific for adenovirus vector antigens were detrimental. We propose that pathogen evasion and dysregulation of host immune responses plays a key role in co-infection associated morbidity. We will test this hypothesis by establishing in vitro and ex vivo co-infection model systems to study pathogen interactions and assess the effect(s) of co-infection on innate signalling and adaptive immune responses. We will develop new approaches to dissect pathogen interactions, ranging from the genesis of fluorescent labelled viruses to state-of-the-art tissue explant models and novel humanised mouse models. Translational studies of co-infected patients will ascertain pathogen-specific effects on innate and adaptive immune responses and the consequences for disease progression. It is imperative that such interactions are elucidated before proceeding with new prophylactic or therapeutic strategies aimed at curtailing pathogen transmission or disease progression in co-infected individuals. We specifically address the call of understanding the basic biology of co-pathogen interactions and immunity.
Project Results:
Distinct clinical Mycobacterium tuberculosis (Mtb) strains have variations in cell wall components, mainly lipids, which can modulate induced immune responses and thereby modulate HIV expression. Genome sequence analysis to detect mutations in 192 Mtb strains collected from HIV infected and uninfected patients in Cape Town, and the use of computational tools to detect and analyse evidence of strain selection helped us identify potential strain with alterations in cell envelope lipid biosynthesis genes. Using liposomes to deliver lipid extracts from selected clinical strain and from precise knockouts strain, and purified lipids we were able to demonstrate that distinct Mtb glycolipids can affect immune responses and HIV infection.

In vitro systems that model hepatic oxygen tensions highlight a role for low oxygen to limit HIV replication at the transcriptional level and are currently studying the role of HIF-regulated metabolites on HIV replication. In addition we identified that the HIV LTR promoter is regulated via HCV E1E2 glycoprotein activation of NF-kB, leading to a reduction in HIV expression. This inhibitory effect was mediated via the E2 protein and we are testing if it can act on bystander cells. We have shown that HCV is capable of infecting colorectal tissue and that this infection affects the mucosal environment inducing a reduction in the level of certain cytokines in contrast to what it is observed with HIV infection of the same tissue. When tissue is infected with both, HCV and HIV, at the same time, the mucosal responses observed are different and replication of HIV is also affected.

We study pathways of infection for two pathogens infecting the liver, the malaria parasite HCV. Plasmodium sporozoites infect the liver and where two host factors are known to contribute to infection, CD81 and SRBI, which are also receptors for HCV. In addition to SRBI and CD81, HCV uses several additional entry factors, including the tight junction proteins Claudin 1 and occludin, the LDL receptor, the Niemann-Pick C1-like (NPC1L1) cholesterol receptor, and the receptor tyrosine kinases EGFR and EphA2. Using various Plasmodium parasites, including species infecting humans, and robust cell culture models, we performed a systematic analysis of the role of HCV entry factors during malaria liver infection. Our data show that Plasmodium and HCV share a limited number of entry factors, namely CD81 and SRBI, but use distinct mechanisms to enter cells. These results have potential implications for the design of new vaccine strategies against malaria.

Infections by HIV, HBV and HCV cause global health problems and where co-infection with multiple viruses induces more severe diseases and higher mortality. We developed mouse model systems to better study these interactions. Our results show that mice with human immune grafts can be mono-infected with HIV or HBV, as well as simultaneously infected with HIV and HBV, constituting a first model system to study co-infections. Our future work will focus on investigating the cross-talk between the host and the virus to unravel the pathophysiology and eventually to test new therapeutic treatments or vaccine strategies. We have also developed a new and more sensitive quantitative assay that allows for the detection of lower copy numbers of proviral DNA than previously achievable which can be utilised when studying these animal models as well as human subjects

We have shown that HCV specific T-cell responses occur in HCV mono-infection compared to HIV-HCV co-infected persons. These responses are inversely correlated with HCV viral load and accelerated liver disease indicated by liver fibrosis. We have identified that HIV-1coinfection hampers HCV CD8 T-cell differentiation. The reduced maturation of HCV-specific CD8 T cells in HIV-1 co-infection associates with reduced T-cell activation. We also demonstrate that HIV-1 reduces HCV-specific CD4 T cell numbers but has no significant effect on anti-HCV B cell responses. Polymorphisms of the host factors DC-SIGN and L-SIGN were successfully linked with risk of HCV transmission but only via the mucosal transmission route and can be linked to expression.

Potential Impact:
The PathCo project addresses the challenge of the call “HEALTH.2012.2.3.2-1: Co-infection of HIV-1/AIDS, malaria, tuberculosis and/or hepatitis.” by establishing in vitro and in vivo model systems to study pathogen co-infection and to translate our observations with clinical material from co-infected subjects. All partners have made significant contributions to understanding the role of host factors in HIV-1, Mtb, Plasmodia and HCV transmission and disease progression. Furthermore, all partner institutions promote translational medicine, providing access to clinical material and the necessary environment to nurture basic and clinical science with necessary multidisciplinary infrastructure that is required to conduct top-rate research at an international level. The consortium has an impressive repertoire of research expertise that will be essential to develop and characterize in vitro and humanized mouse model systems to support pathogen co-infection. Importantly, we have access to well-characterised established cohorts of co-infected patients from different geographical locations. Given the widespread global nature of the pathogens under study it is imperative that we are not biased in our selection of patients and are fortunate to work with cohorts in South Africa, China, The Netherlands and Germany. At its core this project aims to improve our knowledge of the interactions between infectious agents and the host immune responses. The results of these studies will increase our understanding of multi-agent infections and allow more rational design of therapies and vaccines to control HIV-1, TB, malaria and HCV.
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United Kingdom
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