Natural and therapy-induced immune control of HIV-1

Thesis

The human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte (CTL) response is important in the control of HIV-1 infection. Due to the virus having a high rate of mutation, immune pressure can select for variants that are no longer recognised by CTLs to dominate the viral quasispecies. This is similar to how antiretroviral resistance emerges. HIV-1 is therefore adapting to both human leukocyte antigen (HLA)-restricted immune responses and antiretroviral therapy. This thesis initially focused on the natural CTL response to an HLA-B*51-restricted epitope in integrase. This HLA class I allele is associated with slow progression to AIDS; however, as no CTL-driven escape mutation has been fully defined within this integrase epitope, we cannot determine what contributes to the association of HLA-B*51 and natural control of infection. By longitudinally studying a cohort of early HIV-infected individuals, we observed the emergence of polymorphisms that abrogate a CTL response to this epitope. CTL escape may also prove to be the downfall of current immunotherapy strategies attempting to combat HIV infection. T cell receptors (TCRs) have been genetically modified to enhance their binding affinity to an HLA-A*02-peptide complex and transduced into CD8+ cells to create an HIV adoptive therapy. We demonstrate through in vitro selection pressure assays that escape from these cells may be a difficult task for the virus given that the TCR is able to recognise the majority of variants of this epitope. Antigen processing mutations may represent the only option for escape. How this may translate clinically will only be determined through in vivo studies, which must be meticulously monitored. Finally, when this high affinity TCR was fused to an anti-CD3 single chain variable fragment to create proteins capable of redirecting non-HIV-specific CTLs to HIV-infected cells, we found that the result was specific lysis. These proteins may supersede the use of TCR-transduced cells when used in synergy with antiretroviral therapy.

Authors: Yager, N

• Publication date: 2011
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: cytotoxic T-lymphocytes
• Subjects: Infectious diseases; HIV/AIDS; Viruses; Immunology