The metabolism of the HIV-infected CD4+ T cell
Lead Research Organisation:
King's College London
Department Name: Immunology Infection and Inflam Diseases
Abstract
Viruses are not considered life-forms because they lack one defining feature that all other organisms share: metabolism. Being in essence a mobile genetic element, a virus is entirely dependent on the metabolism provided by the host it infects for replication. It is well known that viral infections alter the properties of living cells in order to replicate, often leading to disease. While interactions of viruses with their hosts are well studied at the macro-molecular and cellular level, the demand on small molecule building blocks and energy resources, the metabolites, has seldom been investigated. These demands are potentially conflicting with regard to virus replication and cell survival. Pioneering work on herpes viruses has revealed preferences for the use of certain metabolites during infections, which can be exploited for the development of antiviral drugs by denying the virus a supply of its preferred metabolites. This request for support from the MRC proposes to apply this strategy to HIV-1. HIV-1 infections continue to pose a global health threat and in the absence of a cure or vaccine, patients require antiviral treatment for their entire lives. Current treatments rely heavily on the use of modified building blocks of DNA, which target the viral protein that executes the replication of its genome. This treatment is associated with considerable side effects and can eventually fail owing to the development of resistance by the virus, requiring a switch of medication. Therefore, the development of new and improved agents that target HIV is an ongoing effort. In recent years there has been a great interest in targeting the host components that the virus usurps for its replication, as these are less likely to allow the emergence of viral resistance. We propose to investigate the complex dynamics of metabolites in the HIV infected cell to determine the viral metabolic demand. Our preliminary investigations indicate that we can detect depletion of certain metabolites, notably the amino acids that are the building blocks for proteins, in cells infected with HIV-1. Furthermore, we have observed that HIV alters the activity of mitochondria, which are the metabolic factories of the cell. The funds requested to elaborate on these findings will be targeted towards three main aims, being: i) To provide a comprehensive description of the levels and rate of usage of metabolites in the HIV infected cell, ii) to determine the means by which the virus influences the cellular metabolism and iii) to investigate the feasibility of interfering with metabolic processes on which the virus depends as antiviral drug targets.
Technical Summary
Both treated and untreated HIV-infections are frequently associated with metabolic complications and recent studies are increasingly implicating metabolic factors as predictive for progression to AIDS. However, little is known about the bioenergetic and biosynthetic demands imposed on host cells by HIV-1. As HIV-1 is entirely dependent on the host metabolism, this represents a novel and unexplored target with potential for the development of antiretrovirals. Here, we propose to investigate the metabolism of HIV-infected CD4+ T cells that are the primary target for its replication. In the first instance, differences in the metabolism compared with uninfected cells will be investigated by parallel metabolic and transcriptional profiling using chromatography coupled mass spectrometry, respirometry and microarray technologies. This is expected to reveal viral dependency on specific metabolites and metabolic pathways. Preliminary date included in the proposal support this projection. Following the hypothesis that HIV-1 directly modulates the metabolic state of the cell, an unbiased mutational analysis of all viral proteins will seek to reveal its mode of control. Jointly, these studies will inform experiments that will aim to inhibit HIV-1 replication by interfering with the host-cell metabolism using RNA interference and small molecule inhibitors. Ulitmately, these studies aim to identify targets for the development of antiretrovirals.
Planned Impact
Metabolic processes have been commonly been associated with cancer and neurodegenerative diseases, among others, leading to the development of drugs that target the metabolism for these indications. Investigating the metabolism of the HIV-1 infected cell could reveal similarities between apparently disparate diseases at a metabolic level and may provide clues as to the application of existing treatments to the management of HIV-1. Ultimately, it is hoped that the investigations into metabolic inhibitors particular will translate to a tangible health benefit to the victims of HIV/AIDS. Thus, the proposed work clearly has the potential to impact on the life sciences community in its widest sense, the pharmaceutical industry and the clinical practices associated with the treatment of HIV. Thus, the non-academic beneficiaries of this work would be the clinicians that treat HIV-positive individuals, pharmaceutical companies and the HIV patients. In the first instance, clinicians could benefit from an understanding of viral perturbance metabolic processes as to inform adequate treatment of the metabolic syndrome in HIV patients. The research has the potential to highlight instances where the current treatment of HIV-associated metabolic syndrome may be incompatible with the aim to limit virus replication. This would represent a health benefit to those patients. However, it is expected that such applicable insights would be gained towards the end of the grant period, and will take considerably longer to be developed into clinical practice. Pharmaceutical companies stand to gain from this work by the expected outcome of demonstrating that therapeutic interference with the host metabolism can inhibit HIV-1 replication. This would open up a new class of targets for the development of antiviral drugs. Furthermore, it is conceivable that the work may demonstrate efficacy against HIV of existing drugs that were developed for other indications. Again, this would represent a health-benefit to the patients. Obviously, the time scales for trial and approval of such potential treatments are well beyond the funding period.
People |
ORCID iD |
Hendrik Huthoff (Principal Investigator) |
Publications
Kavanagh Williamson M
(2018)
Upregulation of Glucose Uptake and Hexokinase Activity of Primary Human CD4+ T Cells in Response to Infection with HIV-1.
in Viruses
Hegedus A
(2017)
Evidence for Altered Glutamine Metabolism in Human Immunodeficiency Virus Type 1 Infected Primary Human CD4+ T Cells.
in AIDS research and human retroviruses
Hegedus A
(2014)
HIV-1 pathogenicity and virion production are dependent on the metabolic phenotype of activated CD4+ T cells.
in Retrovirology
Description | King's Health Partners Challenges award |
Amount | £50,461 (GBP) |
Funding ID | R1309155 |
Organisation | King’s Health Partners |
Department | King's Health Partners Research and Development Challenge Fund |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2014 |
End | 01/2015 |
Description | metabolic profiling of HIV patient plasma |
Organisation | GlaxoSmithKline (GSK) |
Country | Global |
Sector | Private |
PI Contribution | processing of patient samples |
Collaborator Contribution | data analysis |
Impact | none as yet |
Start Year | 2014 |
Description | GRC viruses and cells conference, Spain |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Presented a poster at the 2015 GRC viruses and cells |
Year(s) Of Engagement Activity | 2015 |
Description | Microbiology conference, Brazil |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | delivered a talk on the research at the brazilian society of microbiology conference |
Year(s) Of Engagement Activity | 2015 |
URL | http://sbmicrobiologia.org.br/28CBM2015/ |
Description | Pint of science festival |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | This was a presentation to members of the public in a pub, followed by a Q&A session After the talk, I was appraoched by several audience members (some of them university students) to answer questions and provide career/study advice. I have also been asked by the organisers to participate in the festival again next year. |
Year(s) Of Engagement Activity | 2014 |
URL | http://pintofscience.co.uk/ |
Description | Retrovirology meeting, Cambridge, UK |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Delivered a talk on the research at this meeting |
Year(s) Of Engagement Activity | 2015 |
Description | Student placements from local schools for work experience, four students to date one week each |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | four students from local schools have to date come on a work-experience placement in my lab. Two of them have since reported having been offered places at their universities of first choice to study a related subject. |
Year(s) Of Engagement Activity | 2015 |
Description | guest Lecture at Federal University of Rio de Janeiro, Brazil |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | I delivered a guest lecture on metabolic regulation of immune activation and HIV infections to postgradueate and undergraduate students at the Federal univesity of Rio de Janeiro, Brazil. |
Year(s) Of Engagement Activity | 2015 |
Description | metabolism and immunity conference, Ireland |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | PhD student delivered a talk, post-doc presented a poster |
Year(s) Of Engagement Activity | 2015 |
Description | pint of science festival 2015 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | I delivered a lecture entitled "why haven't we cured HIV yet?" to the general public. This served to educate interested members of the public about the obstacles in the way of curing HIV. |
Year(s) Of Engagement Activity | 2014,2015 |
URL | http://pintofscience.co.uk/event/when-viruses-attack/ |
Description | popular science lecture at Walworht Academy, London |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | I delivered a lecture entitled "Why haven't we cured HIV yet?" to pupils of the Walworth Academy, London |
Year(s) Of Engagement Activity | 2015 |
URL | http://walworthacademy.org/ |
Description | practice interviews for medicine studies admission with pupils from Walworth Academy, London |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | performed practice interviews with two pupils from the Walworth academy, London, to prepare them for the admission interviews to study medicine at university |
Year(s) Of Engagement Activity | 2015 |
Description | virology conference UK |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | short talk at the 2014 meeting for recently independent virologists |
Year(s) Of Engagement Activity | 2014 |