Project ID CM-HD2023_34

ThemeCM-HD

Co Supervisor 1A DID/SIMSWebsite

Co Supervisor 1B Immunology & Microbial SciencesWebsite

Manipulation of proinflammatory signaling by accessory proteins Vpu and Vpr in the establishment of viral latency and pathogenesis of HIV/AIDS

Even when viral loads are suppressed by antiretroviral therapy in an infected individual, a small proportion of circulating CD4+ T cells harbour transcriptionally silent Human Immunodeficiency Virus type-1. This latent reservoir can be ‘re-awoken’ by inflammatory stimuli and are thought to be the major barrier to curing someone of HIV-1. HIV-1 replication in CD4+ T cells is regulated by the proinflammatory activation, predominantly via the Nuclear Factor Kappa B (NFkB) family of transcription factors. Two viral proteins, Vpu and Vpr, suppress NFkB activity in distinct parts of the viral life-cycle as a means of innate immune evasion. We hypothesize that their activities may contribute to the establishment of the latent reservoir and thus represent important new therapeutic targets in the search for an HIV-1 cure.

Objectives:
In Yr (1-3), the student will construct dual-reporter HIV-1 viruses expressing mutants of Vpr and Vpu with lesions in NFkB suppressive activity and examine the ability of these virus to establish latent infection in primary CD4+ T cell subsets. Viral integration sites will be sequenced and association with repressive histone modifications will be assessed to determine whether these correlate with the strength of NFkB inhibition. (Yr2) the student will characterize Vpr/Vpu alleles from latent and reactivated viruses form patient samples to assess whether highly active NFkB-suppressing alleles are over-represented in the latent reservoir. In Yr3 the student will assess whether potent Vpu/Vpr alleles impose a barrier to the sustained reactivation of latent HIV-1 by current latency reversing agents being trialled for HIV-1 Cure strategies.

One representative publication from each co-supervisor:

• Galao RP, Wilson H, Schierhorn K, Debeljak F, Hoenen T, Wilson SJ, Swanson CM, Neil SJD (2020) TRIM25 and ZAP target the Ebola Virus ribonucleoprotein complex to promote IFN-mediated restriction. PLOS Pathogens (in press)

• Broadly neutralizing antibody responses in the longitudinal primary HIV-1 infection Short Pulse Anti-Retroviral Therapy at Seroconversion cohort Granger, L. A., Huettner, I., Debeljak, F., Kaleebu, P., Schechter, M., Tambussi, G., Weber, J., Miro, J. M., Phillips, R., Babiker, A., Cooper, D. A., Fisher, M., Ramjee, G., Fidler, S., Frater, J., Fox, J. & Doores, K. J., 1 Nov 2021, In: AIDS (London, England). 35, 13, p. 2073-2084 12 p. Research output: Contribution to journal › Article › peer-review. DOIs: https://doi.org/10.1097/QAD.0000000000002988