New world hemorrhagic fever mammarenaviruses (NWMs) are zoonotic pathogens that cause lethal viral hemorrhagic fevers in humans, for which there are currently no FDA-approved therapies or treatment options. Endemic to South America, these viruses include Junin, Machupo, Guanarito, Chapare, and Sabia, all of which pose significant threats to public health. NWMs display a single tripartite glycoprotein complex (GPC) on their viral surface that is essential for infection. The receptor-binding domain of this complex, GP1, engages the human transferrin receptor 1 (hTfR1) to mediate viral attachment and entry. Despite this conserved receptor dependence, GP1 sequences show only 25%–46% identity across pathogenic strains. This divergence reflects ongoing viral adaptation and complicates the development of broadly neutralizing therapeutics and the prediction of emerging zoonotic variants. To address this, we are applying single-particle cryo-electron microscopy to obtain high-resolution structures of NWM GP1s in complex with hTfR1 and will extend these efforts toward the structural interrogation of engineered disease-relevant variants bridging Machupo and Junin sequences. In parallel, we have characterized interactions between these hybrid GP1 variants and key neutralizing antibodies through binding assays. Together, these studies reveal how sequence adaptation within GP1 balances receptor recognition with immune evasion, providing a blueprint for the rational design of broadly neutralizing GPC-targeted antiviral therapeutics.
Taylor et al. (Sun,) studied this question.
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