By infecting pigtailed macaques (PTMs) with SIVagmsab, we developed a new model of highly pathogenic SIV infection. This model is useful for HIV pathogenesis studies, as it faithfully reproduces classical features of HIV including a high degree of gut dysfunction, persistent immune activation and inflammation (IA/INFL) and high incidence of comorbidities. For model validation, it is critical to determine if available antiretroviral (ARV) therapies control virus replication at levels comparable to those in HIV-infected patients. While SIV is notoriously difficult to control with ARVs, a coformulated combination of three ARVs (reverse transcriptase inhibitors Emtricitabine [FTC] and tenofovir disoproxil fumarate [PMPA] and integrase inhibitor Dolutegravir [DTG]) induces robust virus control in SIVmac239-infected rhesus macaques.
To assess the coformulated therapy efficacy, six SIVagmsab-infected PTMs received the coformulated regimen starting from 48 days post-infection (dpi) and lasting for 11 months. Plasma viral loads were determined by qRT-PCR assay (detection limit: 30 copy/ml). CD4+ T cells in blood, intestine and lymph node, immune activation and inflammation markers were frequently monitored.
SIVagmsab infection peaked at 108-109 copies/ml by 10 dpi and reached a set point of 105-107 copies/ml by 42 dpi. ARV administration resulted in a rapid decline (approx. 2 log) of plasma viremia within 48 hours, with a slower decline occurring over the next 30 days. VLs eventually became undetectable by conventional QRT-PCR between 16 and 164 days post-treatment (dpt), being then relatively well controlled, with only rare blips occurring during the follow-up. ART resulted in a robust restoration of the CD4+ T cells in both intestine and lymph node. Residual immune activation and inflammation were detected in ARV-treated PTMs.
Our results demonstrate that the coformulated ARV regimen administered long-term to an SIV model with extremely high viral loads and severe gut damage is effective in controlling virus replication and results in robust CD4+ T cell restoration. Similar to ARV-treated HIV-infected patients, the PTMs experience residual immune activation and inflammation. Our results thus validate the SIVagmsab model and open large avenues for its use for pathogenesis and treatment studies involving ART.