An investigation of T cell immunity and the HIV reservoir during primary HIV infection : implications for cure strategies

This work focuses on aspects of T cell immunity during the early stages of human immunodeficiency virus (HIV) infection, termed primary infection. Individuals who commence antiretroviral therapy (ART) during primary infection may have preserved immune function, making them a target group for curative strategies. The efficacy of HIV cure interventions are assessed by stopping ART and measuring how long it takes until plasma viraemia recurs. Here, the normal dynamics of this viral rebound in treated and untreated primary infection were characterised, showing that transient control of viral replication is not uncommon at this time. The prospect of HIV cure is heavily reliant on an immune response to eliminate the virus - but such responses become rapidly dysfunctional. During primary infection, changes in T cell activation, memory distribution and the expression of immune checkpoint receptors (which are associated with a type of T cell dysfunction termed exhaustion) occurred. Not all of the demonstrated perturbations in these had normalised following a year of ART which is started during primary infection. This work then turns to the HIV reservoir itself; this is the pool of cells in which the virus persists during long-term therapy and which is the barrier to HIV cure. A longitudinal analysis showed that the size of this reservoir is determined during primary infection where it is linked with aspects of the T cell response measured above. A final chapter shows that CD32, a proposed marker of the reservoir, does not appear to mark cells that comprise the reservoir as specifically as originally reported. Overall this work highlights some of the barriers to current HIV cure strategies and contributes to a body of knowledge which may in the future inform rational design of targeted therapeutic interventions.