The role of Nef in chronic immune activation and the pathogenesis on HIV-1 and HIV-2 infections

Lead Research Organisation: MRC Unit, The Gambia

Abstract

We are trying to understand why in general HIV-2 causes much less disease than HIV-1, even though some people with HIV-2 infection develop AIDS. We want to investigate whether there are important differences in one of the virus proteins called Nef between HIV-1 and HIV-2. We hypothesise that nef in HIV-2 is less likely to cause the immune system to over-react so-called immune activation so we are going to compare nef between HIV-1 and HIV-2, and between healthy people with HIV-2 and those with HIV-2 who have developed AIDS.

Technical Summary

The CD4+ T cell decline in the symptomatic phase of HIV-1 infection is increasingly thought to be the result of the combined viral cytotoxicity and the chronic activation of the immune system. The viral protein Nef has been shown able to promote the activation of infected cells. The molecular mechanism of this effect of Nef is not yet fully understood, but Nef seems to increase the response of infected T cells to activation. HIV-2 infection leads to immunodeficiency with much longer asymptomatic phase and at a much lower frequency than HIV-1 infection. However, HIV-2 appears as cytopathogic as HIV-1. We propose to compare the contribution of HIV-1 and HIV-2 Nef proteins to immune activation. In this regard, we plan to construct plasmids bearing Nef allelic variants from proviral HIV and use them to measure the impact of the Nef variant proteins in T cell and macrophage activation and function (i.e. proliferative response, IL-2 and Th1 or Th2 cytokines release). The project would require the sequencing of nef proviral genes from several patients at different phase of disease, to allow the characterization of the most frequent alleles. Therefore in addition of the study of HIV-2 Nef function, this project would document HIV-2 proviral sequences variations in the Gambia.

Publications

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Fryer HR (2015) Predicting the extinction of HIV-2 in rural Guinea-Bissau. in AIDS (London, England)

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Gourlay AJ (2012) Clinical predictors cannot replace biological predictors in HIV-2 infection in a community setting in West Africa. in International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases

 
Description MRC Strategic Grant
Amount £486,559 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2008 
End 09/2012
 
Title HIV sequences 
Description data on HIV-1 and HIV-2 sequences analysed in the Gambia have been added to the HIV database (Los Alamos) which is publicly available 
Type Of Material Database/Collection of Data/Biological Samples 
Provided To Others? No  
Impact none 
 
Title HIV-1 and HIV-2 sequences 
Description Sequences generated from patient samples collected in China and W. Africa. 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2009 
Provided To Others? Yes  
Impact Sequences submitted to the HIV database in Los Alamos and now publicly available. 
 
Title HIV-2 envelope clones 
Description Full length functional envelope clones generated from HIV-2-infected patients from W. Africa, used for neutralising antibody and other functional studies. 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact Studies of the ability of HIV-2 envelopes to antagonise tetherin are underway in Stuart Neil's lab (GKT). 
 
Title HIV-2 envelope clones 
Description these are full-length HIV-2 envelope clones from W. African patients used in neutralising antibody assays and other functional studies 
Type Of Material Technology assay or reagent 
Year Produced 2010 
Provided To Others? Yes  
Impact work in progress in Stuart Neil's group for tetherin antagonism 
 
Description MRC Gambia/MRC HIU collaboration on HIV-2 infection + infant immunology 
Organisation Medical Research Council (MRC)
Department MRC Unit, The Gambia
Country Gambia 
Sector Public 
PI Contribution Researchers from Oxford have participated in joint projects and have provided training for MRC Gambia staff.
Collaborator Contribution Intellectual partnership on HIV-2 research and infant immunology, logistical support for sample collection and epidemiological/clinical studies, laboratory facilities
Impact All papers listed are joint outputs between MRC Gambia and MRC HIU/Nuffield department of Medicine in either HIV-2 or infant immunology. Successful joint PhD completion for Dr SB in infant immunology. 2 joint HIV-2 PhDs completed.
 
Description Oxford/Gambia HIV-2 collaboration 
Organisation Medical Research Council (MRC)
Department MRC Unit, The Gambia
Country Gambia 
Sector Public 
PI Contribution Training of local technicians and students in the Gambia and during visits to Oxford for specialist research techniques.
Collaborator Contribution Provision of clinical and epidemiological data on long-term HIV-2 clinical and community cohorts, with sample bank. Access to selected samples for analysis. Hosting short-term visits of students and post-docs from our group in the Gambia, provision of access to laboratory facilities.
Impact Several joint publications. Successful completion of jointly supervised PhDs for MRC Gambia staff (Dr CO, Dr LMY).
 
Description Joint MRC/Gambian government meeting on research ethics 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Primary Audience Policymakers/politicians
Results and Impact Research ethics was discussed in a forum which included lay people, policy makers, clinicians and researchers.

None noted
Year(s) Of Engagement Activity 2008
 
Description MRC Gambia Open days 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact open days for the public and study particpants with demonstrations, posters and short talks about the research work of the Unit

none
Year(s) Of Engagement Activity 2006,2007,2008