HIV-2 infection as a comparative lens for functional HIV-1 remission

Four decades into the HIV pandemic, HIV-2 infection remains an underutilized comparative resource for HIV-1 cure research. HIV-2 is associated with lower plasma viral loads, slower CD4⁺ T-cell decline, and delayed disease progression in many individuals. Early studies attributed these features to intrinsic viral attenuation, pointing to differences in accessory protein function, transcriptional regulation, and reservoir size. However, accumulating molecular and epidemiological evidence challenges this interpretation. The transcriptional status of HIV-2 in vivo is not uniform across studies. Some studies report comparable viral RNA levels between HIV-1 and HIV-2 in CD4-matched individuals. In contrast, others find lower per-cell transcriptional output in HIV-2, suggesting that the degree of transcriptional restriction varies with cohort composition, disease stage, and measurement approach. Importantly, neither finding supports a model of uniform proviral silencing. This review examines the molecular biology, immune responses, and reservoir dynamics of HIV-2 infection, weighing evidence that both supports and challenges the view of HIV-2 as an attenuated comparator to HIV-1. The available data suggest that HIV-2 persistence involves regulated viral expression and ongoing, albeit attenuated, immune engagement, rather than transcriptional silence. However, the extent to which immune activation in HIV-2 is quantitatively or qualitatively distinct from that in HIV-1 remains incompletely resolved. HIV-2 does not provide a prescriptive cure blueprint, but it reveals a key biological constraint: ongoing viral transcription can coexist with prolonged immune containment. This finding argues against transcription-only approaches to HIV-1 remission and underscores the need for strategies that combine transcriptional modulation with sustained immune engagement.