Restoring NK cell activity in HIV infected individuals

Restoring NK cell activity in HIV infected individuals

Associated Students: 
Associated Institution: 
University of KwaZulu-Natal (UKZN), Durban, South Africa
Project Trainee Type: 
Email Address: 
kimleighn@gmail.com
Phone Number: 
+27 (0)31-260 4555
Supervisor(s): 

The human leukocyte antigen (HLA) region influences the strength of the immune response to infection and plays a role in various diseases. HLA class I and class II (classical and nonclassical) molecules have been associated with many diseases ranging from those that are caused by infectious agents such as Hepatitis B to those that are associated with autoimmune diseases such as rheumatoid arthritis. The role of various HLA molecules are to present self and non-self-proteins to the immune system. This allows the immune system to distinguish between a cell that is infected by a bacteria, virus or perhaps a tumour cell and one that is healthy. Expression of these molecules on cell surfaces also play a role in determining the strength of the immune responses. For example, in transplantation, mismatching between HLA molecules present on donor tissues and a recipients, can result in rejection of the tissue by the host, in the form of a host immune response [reviewed by (Carey et al., 2019)]. In HIV infection, the HLA region has been shown to correlate with both risk and protection (Pereyra et al., 2010). Recent studies have reported that higher expression of HLA-C on cell surfaces has been associated with lower HIV viral load (Apps et al., 2015). Ramsuran et al., (2018), reported that elevated HLA-A expression results in decreases NK cell activity against HIV infected cells. The mechanism behind this association is based on the interaction of HLA-class I classical and non-classical peptides. HLA class I molecules have a leader sequence that produces a peptide which stabilises the production of the non-classical HLA-E, resulting in higher expression of HLA-E on cell surfaces. HLA-E binds to inhibitory receptors present on NK cells. Interaction between HLA-E and the NK cell inhibitory receptor, NKG2a, prevents NK cells from inducing cytotoxic activity. In conjunction with higher HLA-A expression, individuals with a specific mutation in their HLA-B (HLA-B -21M)(Horowitz et al., 2016) leader sequence, exacerbates the expression of HLA-E.Fisher’s project focusses on restoring NK cell activity in HIV infected samples in-vitro, to reduce viral load. She is investigating the effect of a specific antibody that can block NK cell receptor binding and HLA-E interaction, to increase NK cell killing of HIV infected cells.

Illustration of the influence of varying expression levels of HLA-A  and HLA-B genotypes on NK cell activity in HIV infected cells. This animation also depicts an epigenetic factor known as methylation, that contributes to high and low expression of HLA-A. The more methylation present on the HLA-A gene the lower the expression of that gene. The lower the methylation on the HLA-A  gene, the higher the expression of that gene. The degree of methylation of HLA-A in conjunction with HLA-B -21M genotypes, influences NK cell activities on HIV infected cells [adapted from (Ramsuran et al., 2018)].