Transient Increases in Inflammation and Proapoptotic Potential Are Associated with the HESN Phenotype Observed in a Subgroup of Kenyan Female Sex Workers

• Published in: Viruses Vol. 14; no. 3; p. 471
• Main Authors: Gluchowski, Marcel, Yu, Xiaoqiong, Abrenica, Bernard, Yao, Samantha, Kimani, Joshua, Douville, Renée N., Ball, Terry Blake, Su, Ruey-Chyi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 25.02.2022; MDPI
• Subjects: antiviral; Antiviral Agents; Antiviral drugs; Apoptosis; CD4 antigen; Female; females; Genotype & phenotype; HESN; HIV; HIV Infections; HIV-1; Human immunodeficiency virus; Humans; IFN-γ; Infections; Inflammation; Interferon regulatory factor 1; ISG; Kenya; Leukocytes, Mononuclear; Lymphocytes; Lymphocytes T; Mucosal immunity; PBMC; Peripheral blood mononuclear cells; Phenotype; Phenotypes; Regulation; Sex industry; Sex Workers; Sexual behavior; Transcription; transcription (genetics); Viral infections; γ-Interferon; Kenya; Nairobi Kenya; Canada; HIV-1; commercial sex workers; IFN-γ; antiviral; HESN; ISG; PBMC
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v14030471

Interferon (IFN) -stimulated genes (ISGs) are critical effectors of IFN response to viral infection, but whether ISG expression is a correlate of protection against HIV infection remains elusive. A well-characterized subcohort of Kenyan female sex workers, who, despite being repeatedly exposed to HIV-1 remain seronegative (HESN), exhibit reduced baseline systemic and mucosal immune activation. This study tested the hypothesis that regulation of ISGs in the cells of HESN potentiates a robust antiviral response against HIV. Transcriptional profile of a panel of ISGs with antiviral function in PBMC and isolated CD4+ T cells from HESN and non-HESN sex worker controls were defined following exogenous IFN-stimulation using relative RT-qPCR. This study identified a unique profile of proinflammatory and proapoptotic ISGs with robust but transient responses to exogenous IFN-γ and IFN-α2 in HESN cells. In contrast, the non-HESN cells had a strong and prolonged proinflammatory ISG profile at baseline and following IFN challenge. Potential mechanisms may include augmented bystander apoptosis due to increased TRAIL expression (16-fold), in non-HESN cells. The study also identified two negative regulators of ISG induction associated with the HESN phenotype. Robust upregulation of SOCS-1 and IRF-1, in addition to HDM2, could contribute to the strict regulation of proinflammatory and proapoptotic ISGs in HESN cells. As reducing IRF-1 in the non-HESN cells resulted in the identified HESN ISG profile, and decreased HIV susceptibility, the unique HESN ISG profile could be a correlate of protection against HIV infection.