In contrast to the worldwide pandemic of HIV-1 infection, the second AIDS virus, HIV-2, has remained largely confined to West Africa and appears to be falling in prevalence1. Despite a very similar size and gene organisation, as well as approximately 30-60% amino acid homology between HIV-1 and HIV-2, the epidemiology and clinical features of infection with the two viruses are very different. In one cohort in Guinea-Bissau, 35-40% of untreated HIV-2-infected people maintained an undetectable viral load for over a decade and had a normal lifespan2. HIV-2 infection could therefore be seen as an attractive model of a “functional cure” for HIV-1 cure strategies, i.e. natural control of HIV replication without anti-retroviral therapy (ART) – a rare occurrence in HIV-1 infection3. In support of this approach, prior HIV-2 infection has been shown to protect against HIV-1 disease progression, although the mechanisms remain unclear 4. On the other hand, HIV-2-infected progressors develop AIDS without treatment in a very similar way to HIV-1-infected subjects.
Previous studies from our group showed that viral control in HIV-2-infected people was strongly associated with potent cytotoxic T lymphocyte (CTL) responses directed towards conserved regions of the HIV-2 capsid protein, which were absent in over half of HIV-2 progressors5,6. Viral control has also been linked to the presence of HIV-2 capsid sequences that increase the susceptibility of the virus to restriction by the host restriction factor TRIM5a. TRIM5a binds to incoming viral capsids in the cytoplasm, causing premature uncoating and leading to proteasomal degradation of the TRIM-capsid complex. HIV-2 is generally more susceptible to TRIM5a restriction than HIV-17, which may partly explain the differences in clinical outcomes between the two viruses. Moreover, the HIV-2 capsid sequences associated with viral control lead to enhanced proteasomal processing of “protective CTL epitopes”8.
For this PhD project, we propose to investigate the hypothesis that particular combinations of susceptible HIV-2 capsids and variants of TRIM5a lead to potent viral restriction, which in turn may lead to the generation of effective CTL responses. In the Guinea-Bissau community HIV-2 cohort, we have identified novel single nucleotide polymorphisms (SNPs) within TRIM5a that show significantly more potent activity against HIV-2 and SIV in vitro (Jallow, ms in preparation).
This project will involve a combination of bioinformatic analysis, to determine the combinations of capsid and TRIM5a sequences from HIV-2-infected subjects that are associated with good outcomes. Functional studies will be used to determine whether these combinations lead to effective restriction in vitro, and structural studies will be used to examine the impact of TRIM5a restriction on HIV-2 capsid disruption using cryo-electron microscopy (cryoEM) 9. The following questions will be addressed:
Material and methods: Samples collected from HIV-2 cohorts in Guinea-Bissau
2. Do these combinations lead to potent TRIM5a restriction of HIV-2 infected cells in vitro?
Material and Methods: Cell-lines transfected with TRIM5a variants in restriction assays of molecular clones of HIV-2 engineered to express particular capsid sequences
3. How does variation in TRIM5a and HIV-2 capsid impact on the destruction of viral cores, and where is the exact site of action within the infected cell?
Material and Methods: Visualisation by cryoEM and cryo-electron tomography
1. da Silva, Z.J., et al. Changes in prevalence and incidence of HIV-1, HIV-2 and dual infections in urban areas of Bissau, Guinea-Bissau: is HIV-2 disappearing? AIDS 22, 1195-1202 (2008).
2. Schim van der Loeff, M.F., et al. Undetectable plasma viral load predicts normal survival in HIV-2-infected people in a West African village. Retrovirology 7, 46 (2010).
3. Fauci, A.S., Marston, H.D. & Folkers, G.K. An HIV cure: feasibility, discovery, and implementation. JAMA 312, 335-336 (2014).
4. Esbjornsson, J., et al. Inhibition of HIV-1 disease progression by contemporaneous HIV-2 infection. N Engl J Med 367, 224-232 (2012).
5. de Silva, T.I., et al. Correlates of T-cell-mediated viral control and phenotype of CD8(+) T cells in HIV-2, a naturally contained human retroviral infection. Blood 121, 4330-4339 (2013).
6. Leligdowicz, A., et al. Robust Gag-specific T cell responses characterize viremia control in HIV-2 infection. J Clin Invest 117, 3067-3074 (2007).
7. Ylinen, L.M., Keckesova, Z., Wilson, S.J., Ranasinghe, S. & Towers, G.J. Differential restriction of human immunodeficiency virus type 2 and simian immunodeficiency virus SIVmac by TRIM5alpha alleles. J Virol 79, 11580-11587 (2005).
8. Jallow, S., et al. The presence of prolines in the flanking region of an immunodominant HIV-2 gag epitope influences the quality and quantity of the epitope generated. Eur J Immunol 45, 2232-2242 (2015).
9. Zhao, G., et al. Rhesus TRIM5alpha disrupts the HIV-1 capsid at the inter-hexamer interfaces. PLoS Pathog 7, e1002009 (2011).
This project provides an opportunity for training in host genetics, cellular immunology, bioinformatics and structural biology. The SRJ lab is housed with other HIV immunology groups in the NDM Research Building, where there are weekly scientific presentations both for the SRJ lab and for the HIV groups as a whole, as well as journal clubs and frequent seminars. Students are encouraged to attend and present their work at national and international meetings. The PZ lab is part of the Structural Biology Division (STRUBI) within the Wellcome Trust Centre for Human Genetics, where the state-of-the-art cryoEM instrument are housed, along with other structural virology groups.
Project reference number: 960
|Professor Sarah L Rowland-Jones||Target Discovery Institute||Oxford University, NDM Research Building||GBRemail@example.com|
|Professor Peijun Zhang||Structural Biology||Oxford University, Henry Wellcome Building of Genomic Medicine||GBRfirstname.lastname@example.org|
|Dr Joakim Esbjornsson||NDM||Oxford University||GBRemail@example.com|
There are no publications listed for this DPhil project.