Extreme clinical phenotypes

Within the 2000HIV cohort of people living with HIV are normal progressors, individuals with an expected disease progression and proper response to combination antiretroviral therapy (cART). However, around 6% of included participants in the study have a specific phenotype in which they are able to spontaneously control replication of the HIV. In contrast, there are also around 8.5% immunological non-responders, who fail to properly restore normal CD4 T-cell counts after initiation of cART. Studying these specific HIV clinical phenotypes may provide insights into the mechanisms and pathways involved in the immune system’s response to HIV and the effects it has during chronic infection in people living with HIV.

Elite controllers (ECs) consist of a small group of people living with HIV with the ability to spontaneous control HIV replication over a long period of time in the absence of antiretroviral therapy. ECs have therefore been extensively studied as they may improve our insight how the human immune system controls HIV. This capacity of ECs to control HIV has been attributed so far to the immune system and its ability to build responses with enhanced functionality. Responses of T-lymphocytes (CD8+ and follicular T helper), natural killer and dendritic cells together with the presence of specific HLA class I and HIV-1 antibodies have been associated with protection against HIV.

Studies in ECs offer a unique opportunity to improve our understanding how the (innate) immune system may control HIV. In the current study, a significant number of ECs have been included, consisting of a total of 114 (34 elite and 80 viremic). By performing systems biology, combining large-scale analysis of multiple ‘omics’ databases with functional immunology, we aim to perform in depth characterization of ECs. Moreover, we aim to apply our knowledge and expertise on innate immunity programs to further understand how the initial steps that takes place in the earlier phase during of HIV acquisition contributes to the development of long-lasting protective responses against the virus. Within the context of 2000HIV, a sub-study was performed in which we included Elite controllers and their first degree relatives and compared omics data with normal progressors and their family members. The inclusion of family members has the aim to study mechanisms that drive elite controller status without the effect of HIV.

The data generated in our project will extend the knowledge on ECs and may open new avenues for new interventions for long-term prevention and control of HIV.