Introduction: Since the identification of HIV, several studies reported the unusual case of small groups of subjects showing natural resistance to HIV infection. These subjects are referred to as HIV-1-exposed seronegative (HESN) individuals and include people located in different areas, with diverse ethnic backgrounds and routes of exposure. The mechanism/s responsible for protection from infection in HESN individuals are basically indefinite and most likely are multifactorial.Areas covered: Host factors, including genetic background as well as natural and acquired immunity, have all been associated with this phenomenon. Recently, epigenetic factors have been investigated as possible determinants of reduced susceptibility to HIV infection. With the advent of the OMICS era, the availability of techniques such as GWAS, RNAseq, and exome-sequencing in both bulk cell populations and single cells will likely lead to great strides in the understanding of the HESN mystery.Expert opinion: The employment of increasingly sophisticated techniques is allowing the gathering of enormous amounts of data. The integration of such information will provide important hints that could lead to the identification of viral and host correlates of protection against HIV infection, allowing the development of more effective preventative and therapeutic regimens.
Keywords: Epigenetic; HESN; HIV-1 resistance; OMICS approaches; miRNA; polymorphisms.