Regulatory NLRs in HSV-1 Infection: Direct Evidence, Comparative Mechanisms and Testable Hypotheses.

Herpesviruses establish lifelong persistence through acute replication, immune evasion, latency, and reactivation. Nucleotide-binding oligomerization domain-like receptors (NLRs) are most commonly discussed in the context of inflammasome sensors, pyroptosis, and IL-1 family cytokines. Here, we depart from this canonical framework to focus on three regulatory NLRs-NLRC3, NLRC5, and NLRX1-that act outside inflammasome assembly. Using HSV-1 as the central model and other herpesviruses as comparators, we propose a conceptual framework in which these NLRs modulate three host-control layers: cGAS-STING-dependent DNA sensing, MHC class I antigen presentation, and MAVS-mediated mitochondrial antiviral signaling. We explicitly frame these NLRs as regulatory hypotheses for HSV-1 biology rather than established restriction factors, and we provide prioritized, falsifiable predictions to guide future experimentation. Current evidence is strongest at the pathway level; direct tests of NLRC3, NLRC5, and NLRX1 in acute infection, latency, and reactivation remain necessary. The evidence is asymmetric: NLRC3 has been functionally tested in HSV-1-infected cells and mice, whereas direct HSV-1 regulation by NLRC5 or NLRX1 remains unestablished. Comparative herpesvirus and pathway studies, therefore, support testable hypotheses for NLRC5 and NLRX1 in acute infection, latency and reactivation.