Influence of the intracellular environment on HIV-1 replication and its modulation by innate cytokines

Thesis

The lack of effective immune-based prophylactic and therapeutic strategies to combat human immunodeficiency virus type 1 (HIV-1) prompts a need for a better understanding of determinants of in vivo viral control by host responses. Type I interferons (IFNs) are pleiotropic innate cytokines with antiviral and immunomodulatory properties that restrict HIV-1 replication early after infection and also drive detrimental chronic immune activation. By contrast, the involvement of type III IFNs, a related family of innate IFNs, in in vivo HIV-1 control is less well understood. Furthermore, HIV-1 inhibition by innate IFNs is typically studied in in vitro models that do not reflect conditions at in vivo sites of viral replication, where many CD4+ T cell targets are not highly-activated and oxygen tension is low. Work in this thesis aimed to determine the contribution of type III IFNs to HIV-1 control in acute infection, and elucidate the interplay between CD4+ T cell activation, oxygen availability and type I IFNs in determining levels of productive HIV-1 replication in primary CD4+ T cells.

HIV-1 infection was found to trigger much less systemic upregulation of type III IFN than of IFN-α (a type I IFN). Type III IFNs also inhibited HIV-1 replication in activated CD4+ T cells much less effectively than type I IFNs, primarily due to the low expression of their receptor on these cells. Type I IFN-mediated inhibition of HIV-1 replication in CD4+ T cells was dependent on the T cell activation state, with less activated CD4+ T cells showing reduced responsiveness to IFN-λ2. CD4+ T cells stimulated under low oxygen conditions (1% O2) underwent less phenotypic activation and proliferation and had a lower capacity to support productive HIV-1 replication than cells in atmospheric (21%) O2. They also exhibited lower type I IFN receptor expression and signalling, which compromised IFN-α-mediated control of viral replication. These findings provide new insights into determinants of HIV-1 replication in CD4+ T cells and its control by innate IFNs, and suggest directions for future research to develop improved HIV-1 therapies.

Authors: Ismed, DR

• DOI: 10.5287/ora-44obonjdd
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: interferon lambda; activation; viral replication; cytokines; interferon alpha; CD4+ T cell; HIV; interferon signalling; oxygen
• Subjects: Virology; Natural immunity; HIV infections; Interferon; Immunology