Disease progression in Human Immunodeficiency Virus type 1 infected viraemic controllers

Abstract

Background: The mechanism of CD4+ T-cell decline in Human Immunodeficiency Virus-1 (HIV-1) infection is unclear, but the association with plasma HIV-1 RNA-load suggests viral replication is involved. Viraemic controller patients with low HIV-1 RNA-loads (<2000 copies/ml) typically maintain good CD4+ T-cell counts (>450 CD4+ T-cells/mm3). However, within a cohort of 86 viraemic controllers, a subgroup (18 ‘discord controllers’) was identified with low CD4+ T-cell counts (<450 CD4+ T-cells/mm3) which present clinical uncertainty. The underlying mechanism accounting for CD4+ T-cell decline in the face of low or undetectable HIV-1 RNAloads is unknown. The objective of the work described in this thesis was to investigate the virological and host immune system dynamics in discord controllers compared with typical controllers. Method Epidemiological features, HIV-1 subtype, cellular HIV-1 DNA-load, T-cell populations (CD4+/CD8+ naïve/ central-memory/ effector-memory subsets; CD45RA/RO ± CD62L) and Tcell activation markers (CD38, HLA-DR) were examined for discord controllers and typical controllers as well as progressors with HIV-1 RNA-load >10000 copies/ml, <450 CD4+ Tcells/ mm3. Results Discord controllers and typical controllers were similar, based on epidemiological features and viral subtype distribution. They resembled progressors, showing high HIV-1 DNA-load, depletion of naïve CD4+ T-cells and higher activation in all CD4+ T-cell subsets. However, the CD8+ T-cell compartment in discord controllers was similar to typical controllers with preserved naïve CD8+ T-cells and low level CD8+ T-cells activation. Conclusion The data presented in this thesis is consistent with a relationship between CD4+ T-cell activation, HIV-1 DNA-load and disease progression but not HIV-1 RNA-load. This suggests that in viraemic controllers, HIV-1 DNA-load may be a better marker of viral replication and disease progression than HIV-1 RNA-load. Furthermore, low level CD8+ T-cell activation correlate with low plasma HIV-1 RNA-load but not with HIV-1 DNA-load.