Testicular toll with viral intrusion: Molecular insights into the impact of chronic HIV infection on male fertility.

backgroundHuman immunodeficiency virus (HIV) infection remains a major global health concern, compromising immune function and increasing susceptibility to opportunistic infections. Over the past two decades, fertility desire among people living with HIV has remained low due to poor health, fear of transmission and restrictive reproductive policies. In men, particularly those in advanced stages of infection, HIV has been associated with profound alterations in semen quality, including reduced ejaculate volume, impaired sperm motility, abnormal morphology and increased incidence of sperm aneuploidy factors that collectively contribute to male infertility.

methodsThis study explored the molecular mechanisms of HIV-associated male infertility using a preclinical HIV-1 transgenic (Tg) rat model. Real-time PCR (RT-PCR) and protein expression analyses were performed to evaluate the expression of cation channels of sperm (CatSper 1-4), along with mitochondrial and inflammatory gene networks. Histopathological examination, computer-assisted semen analysis (CASA), nuclear morphology assessment, and transcriptomic sequencing were used to characterize structural, functional, and molecular alterations in the testes and sperm of Tg animals.

resultsRT-PCR and protein expression analyses revealed marked downregulation of CatSper1-4 channels, along with dysregulation of mitochondrial and inflammatory gene networks in the testes of Tg animals. Histopathological examination further demonstrated structural disruptions within the seminiferous tubules of Tg rats. Functional assessments using CASA and nuclear morphology analysis confirmed reduced motility and abnormal sperm morphology in Tg rats. Complementary transcriptomic sequencing identified novel gene signatures and disrupted pathways associated with testicular dysfunction in Tg rats.

conclusionCollectively, our findings demonstrate that HIV-1 transgene expression impairs sperm production and function at both mRNA and protein levels by disrupting ion channel regulation and perturbing broader molecular pathways, ultimately contributing to male infertility. This study provides clinically relevant insights into reproductive complications in HIV-infected individuals and may inform future therapeutic strategies. KEY POINTS: HIV-1 transgene expression impairs testicular architecture and spermatogenesis. CatSper 1-4 channels downregulation is associated with impaired sperm function. Mitochondrial dysfunction and altered immune signaling pathways accompany abnormal sperm functions. HIV-1 transgenes induce profound abnormalities in sperm morphology, motility, and widespread transcriptional remodeling of reproductive pathways.