Nineteen annotated and 24 undefined transcriptional modules constitute a robust transcriptional signature that collectively distinguished early AHI patients from non-infected controls. The activity of transcriptional modules related to interferon, cell cycle, cytotoxic, and mitochondrial responses were significantly increased in AHI patients. At study enrollment, the intensity of this signature was not correlated with viral load and exhibited heterogeneity between patients. Association between viral load and signature intensity was found over time. However, three patients exhibited little change in transcriptional activity despite high viral loads. When compared to acute RSV and Influenza infections, only interferon signatures were conserved across all three infections while cell cycle, cytotoxic, and mitochondrial responses were unique to AHI. The AHI signature of untreated patients regressed to non-infected control levels by 12–24 weeks post enrollment. The initiation of ART accelerated the dissipation of this signature, returning the core AHI signature to normal levels within 4 weeks.