Leishmania RNA Virus and Its Impact on Drug Response and Clinical Outcomes in Leishmaniasis: A Comprehensive Review.

Leishmania RNA viruses (LRVs) have emerged as significant modulators of disease severity, therapeutic response, and clinical outcomes in various forms of leishmaniasis. This review provides a comprehensive overview of the current knowledge surrounding LRV1 and LRV2, focusing on their taxonomy, molecular biology, epidemiological patterns, and pathogenic roles across Leishmania species. LRV1, predominantly infecting New World Leishmania (Viannia) species such as L. guyanensis and L. braziliensis, and LRV2, primarily associated with Old World species such as L. major, L. tropica, and L. infantum as viral endosymbionts, have both been associated with increased mucocutaneous dissemination, treatment failure, and disease relapse. Mechanistically, these viruses enhance parasite virulence through immune modulation-particularly via Toll-like receptor 3 (TLR3)-leading to chronic inflammation and host tissue damage. The presence of LRV has been correlated with unresponsiveness to first-line treatments such as meglumine antimoniate and amphotericin B, especially in endemic regions. Furthermore, LRV may serve as a prognostic biomarker, and its detection could guide therapeutic decision-making in high-risk patients. The review also discusses emerging therapeutic strategies targeting viral components, such as capsid proteins and RNA-dependent RNA polymerase, as well as vaccine development using recombinant viral antigens. Finally, it emphasizes the urgent need for expanded surveillance, standardized diagnostics, and deeper exploration of host-virus-parasite interactions to better understand the clinical and epidemiological impact of LRV-positive leishmaniasis.