Expression of Human Endogenous Retroviruses in Peripheral Blood of Acute and Chronically HIV-Infected Subjects and Effect of Antiretroviral Therapy

Human endogenous retroviruses (HERVs) originate from ancient retroviral integration into the primate germline. Although most are defective proviruses, the most recently endogenized groups, like the HERV-K family, retain intact ORFs encoding retroviral proteins. HERVs usually remain transcriptionally silent, yet this status is reversible. Multiple HIV-HERV interactions, mainly mediated by the HIV Tat protein, lead to HERV transcription and protein production. The present study investigates HERV-K transcription in particular of Human MMTV-like (HML) group-2 and 6 in peripheral blood of people with HIV (PWH). Using different experimental approaches—such as single-cell and plasma transcriptomics-, we found that HERV-K transcripts may be detected during both acute and chronic phases of the infection, with HML-6 showing higher expression compared to HML-2, predominantly within myeloid cells. Effective combined antiretroviral therapy (cART) was able to significantly reduce HML-6 transcription, regardless of whether the treatment was initiated in the acute or late chronic phases of HIV infection. Notably, chronic infections showed higher HML-6 transcript levels compared to acute infections in both naïve and successfully cART-treated subjects, potentially associated with persistent immune dysregulation observed in chronic HIV infection, although a direct causal role of HML-6 expression remains to be established.