Understanding the impact of hypoxia on HIV replication and latency

Project Overview

Background:  

 

The lentivirus human immunodeficiency virus type 1 (HIV-1) is not effectively contained by the host immune response, and although currently-available anti-retroviral agents control viral replication and can prevent progression to AIDS they fail to eradicate integrated copies of the viral genome that provide a long-lived cellular reservoir of infection. This necessitates lifelong treatment which is costly and often poorly adhered to; and even if near-complete suppression of virus replication is maintained, ongoing HIV-1 persistence drives chronic inflammation and immune dysfunction with detrimental effects on health.  An increased understanding of factors that regulate HIV-1 replication and reactivation from latent sites is needed to inform the development of new strategies to control/eradicate HIV-1.

Viruses are obligate intracellular parasites that replicate in different host cells/tissues, where nutrient and oxygen supplies can vary. Oxygen tensions differ across tissues, e.g. CD4+ T cells (the principal site of HIV-1 replication and latency) exist in a hypoxic environment in lymphoid tissues (1% O2) whilst circulating CD4+ T cells encounter variable oxygen tension as they traffic around the body (13% O2 in arterial blood). Viruses have evolved to exploit hypoxic cellular metabolism to replicate or persist in their host. Hypoxia Inducible Factors (HIFs) enable a cell to respond to low oxygen stress signals and regulate a wide range of genes involved in energy metabolism and inflammation. We recently showed that a low oxygen environment inhibits HIV-1 replication in CD4+ T cells at the transcriptional level. HIFs regulate host cell transcriptional events via binding hypoxic responsive elements (HRE) in the promoter or enhancer elements of target genes. We have identified a HRE within the HIV-1 promoter that is conserved across all viral genotypes published to date, providing a mechanism for HIFs to directly regulate HIV-1 replication.

This project will explore the hypothesis that HIF-signalling regulates HIV-1 transcription and reactivation from latency. The following unanswered questions will be addressed:

Training Opportunities

The student will join an experienced team of scientists with expertise in HIV immunology and hypoxia biology, providing an ideal environment for this project. State-of-art HIV replication model systems, HIF KO cells are available for this study. Training will be provided in all relevant experimental and analytical aspects of the project. 

Theme

Immunology & Infectious Disease

Admissions

Project reference number: 952

Funding and admissions information

Supervisors

Name Department Institution Country Email
Professor Jane McKeating NDM Research Building Oxford University, NDM Research Building GBR jane.mckeating@ndm.ox.ac.uk
Professor Persephone Borrow NDM Research Building Oxford University, NDM Research Building GBR persephone.borrow@ndm.ox.ac.uk

There are no publications listed for this DPhil project.