Durable suppression of HIV-1 with resistance mutations to integrase inhibitors by dolutegravir following drug washout.

OBJECTIVES: Dolutegravir (DTG) has achieved better long-term suppression of HIV-1 replication than other integrase strand transfer inhibitors (INSTIs), such as raltegravir (RAL) and elvitegravir (EVG). In in-vitro drug washout experiments, we previously showed that removal of DTG from pretreated MT-2 cells infected with wild-type HIV-1 showed slower rebound in viral replication as compared to removal of RAL. Now, we performed DTG, EVG and RAL washout experiments to compare the recovery of viral integration and production of 2-long terminal repeat (LTR) circles using wild-type HIV-1 clones, R263K viruses with low-level resistance to DTG and viruses with G140S/Q148H mutations showing cross-resistance against all currently approved INSTIs.

DESIGN AND METHODS: MT-2 cells infected with wild-type, R263K or G140S/Q148H HIV-1 clones were treated with DTG, RAL or EVG for 3 days. Viral rebound following drug washout was assessed, monitoring viral integration and 2-LTR circle production by qPCR.

RESULTS: Viral integration did not resume for up to 8 days after DTG washout from the wild-type or R263K infections but increased soon after washout of either RAL or EVG. With the G140S/Q148H virus, levels of integration were not significantly affected by the presence of either RAL or EVG. With DTG, integration was much lower at 3 days after infection than for the no-drug control. At 8 days after DTG washout, viral integration resumed but remained relatively low.

CONCLUSION: DTG antiretroviral activity in tissue culture is more durable than that of either RAL or EVG after drug washout and this is true for both wild-type and drug-resistant viruses.