Dolutegravir inhibits HIV-1 Env evolution in primary human cells.

In treatment-naive HIV-positive individuals, the integrase strand-transfer inhibitor dolutegravir (DTG) has not been associated with emergent drug-resistance mutations, neither against this drug nor against other antiretroviral drugs that were used in combination with it. This is in contrast to all other antiretroviral drugs tested so far, including the integrase strand-transfer inhibitors raltegravir (RAL) and elvitegravir that can lead to treatment failure with the emergence of drug-resistance mutations. These observations suggest that DTG may provide an additional protection against resistance compared to other drugs by decreasing HIV-1 genetic evolution. Here, we tested this hypothesis by measuring the genetic and amino-acid diversity of Env/gp160 from two HIV-1 primary isolates that were grown in the presence of increasing concentrations of DTG or RAL over the course of 38-55 weeks. The results show that treatment with DTG led to less HIV-1 genetic and amino-acid diversification over time, as compared to treatment with RAL or the absence of drug. These results may help to explain the absence of emergent resistance mutations in treatment-naive individuals treated with DTG.