Genetic and epigenetic regulation of natural resistance to HIV-1 infection: new approaches to unveil the HESN secret

ABSTRACT

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
• miRNA
• OMICS approaches
• polymorphisms

Article Highlights

• A characteristic feature of every infectious disease is that not all exposed individuals become infected.

• The relative contribution of genetic polymorphisms to the phenomenon of natural resistance to HIV-1 infection has been ascertain for some genes and new pathways are currently under investigation (Antigen presentation, Vitamin D, Interferon λ genetic variants among others)

• Epigenetics is a new emerging research area whose contribution to progression of HIV-1 infection has been recently investigated. Only one report has so far explored the role of epigenetics in natural resistance to HIV-1 infection in highly exposed seronegative (HESN) individuals. Further analyses in this direction are therefore mandatory.

• MicroRNAs (miRNAs) represent a post-transcriptional regulation mechanism responsible for changes in gene expression. In the field of HIV-1 infection, miRNA target genes include both viral and host gene transcripts, exerting a direct or indirect control of viral replication, respectively.

• MiRNA profiling in cellular subsets from individuals displaying different susceptibility to HIV-infection is crucial to elucidate their role in controlling resistance to HIV-1 infection and HIV-1 replication competence.

• The setting up of more and more sensitive OMIC techniques such as GWAS, RNAseq, miRseq, proteomic, metabolomic in bulk cell populations as well as single-cell subtypes will result in the generation of a plethora of data that could explain the observed different susceptibility to HIV-1 infection/progression to disease.

• The integration of data obtained with these novel sophisticated technologies will allow the identification of new variants/pathways responsible for the atypical HESN phenotype. Such potential targets could be exploited in the fine-tuning of vaccine/drugs for HIV-infection.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.