Early-life gammaherpesvirus infection results in an expanded long-term latent reservoir.
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Gammaherpesviruses are ubiquitous oncogenic pathogens that establish lifelong latency, are associated with multiple types of malignancies, and are increasingly believed to play a role in autoimmune disease. Human Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) frequently infect across various stages of childhood development. Nevertheless, how infection during the earliest stages of life, when immune defenses are still developing, shapes the risk of malignant disease and autoimmunity remains poorly understood. Here, we characterized acute and chronic infection following early-life inoculation with murine gammaherpesvirus 68 (MHV68). We infected mice at postnatal day P3, P5, or P8, ages that, in the compressed developmental timeline of the mouse model, correspond to the progressive immune maturation that occurs in human neonatal to infancy stages. Mice infected during early life displayed age- and dose-dependent susceptibility to MHV68 infection, with the approximate lethal dose 50% (LD50) values ranging from 200 plaque forming units (PFU) in mice inoculated at P3 to 10,000 PFU in mice inoculated at P8. Severe disease was accompanied by substantial weight loss prior to death. Following intranasal inoculation of P8 pups, MHV68 replicated rapidly in the lung, reaching high titers by 3 days, achieving higher lung titers than adult mice at 5 days. Nevertheless, acute replication was largely resolved by 16 days in surviving animals. Early-life infection induced splenomegaly and resulted in the establishment of latency at frequencies similar to those of adult mice. In contrast, mice infected as neonates maintained 14-fold higher frequencies of latently infected cells than adults during the long-term stable phase of latency, months after clearance of a lytic infection, suggesting that early-life infection substantially alters the long-term latent reservoir. Together, these data demonstrate for the first time that gammaherpesvirus exposure during early life imprints a long-lasting increase in latency burden and establishes a foundation to determine potential implications for malignancy and autoimmune risk later in life.