Nat Med. 2018 Sep; 24(9):1430-1440.

PubMed ID: 30082858

Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound

Okoye AA, Hansen SG, Vaidya M, Fukazawa Y, Park H, Duell DM, Lum R, Hughes CM, Ventura AB, Ainslie E, Ford JC, Morrow D, Gilbride RM, Legasse AW, Hesselgesser J, Geleziunas R, Li Y, Oswald K, Shoemaker R, Fast R, Bosche WJ, Borate BR, Edlefsen PT, Axthelm MK, Picker LJ, Lifson JD

Prophylactic vaccination of rhesus macaques with rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) elicits immune responses that stringently control highly pathogenic SIV infection, with subsequent apparent clearance of the infection, in ~50% of vaccinees. In contrast, here, we show that therapeutic RhCMV/SIV vaccination of rhesus macaques previously infected with SIV and given continuous combination antiretroviral therapy (cART) beginning 4-9 d post-SIV infection does not mediate measurable SIV reservoir clearance during over 600 d of follow-up on cART relative to RhCMV/control vaccination. However, none of the six animals started on cART on day four or five, across both RhCMV/SIV- and RhCMV/control-vaccinated groups, those rhesus macaques with SIV reservoirs most closely resembling those of prophylactically RhCMV/SIV-vaccinated and protected animals early in their course, showed post-cART viral rebound with up to nine months of follow-up. Moreover, at necropsy, these rhesus macaques showed little to no evidence of replication-competent SIV. These results suggest that the early SIV reservoir is limited in durability and that effective blockade of viral replication and spread in this critical time window by either pharmacologic or immunologic suppression may result in reduction, and potentially loss, of rebound-competent virus over a period of ~two years.