Dolutegravir inhibits HIV-1 Env evolution in primary human cells

Area of Science:

• Virology
• Immunology
• Pharmacology

Background:

• Integrase strand-transfer inhibitors (INSTIs) like dolutegravir (DTG) are crucial in HIV treatment.
• Emergence of drug-resistance mutations is a significant challenge with antiretroviral therapies.
• DTG has shown a lack of associated resistance mutations in treatment-naive individuals, unlike other INSTIs such as raltegravir (RAL) and elvitegravir.

Purpose of the Study:

• To test the hypothesis that DTG decreases HIV-1 genetic evolution, providing enhanced protection against drug resistance.
• To compare the impact of DTG versus RAL on HIV-1 genetic and amino-acid diversity.

Main Methods:

• Two HIV-1 primary isolates were cultured in vitro with increasing concentrations of DTG or RAL.
• Viral genetic and amino-acid diversity of Env/gp160 was measured over 38-55 weeks.
• Diversification was compared between DTG, RAL, and no-drug control groups.

Main Results:

• DTG treatment resulted in significantly less HIV-1 genetic diversification compared to RAL treatment.
• Amino-acid diversification was also lower in the DTG group.
• Both DTG and RAL were compared against a no-drug control, with DTG showing superior resistance-mitigating effects.

Conclusions:

• DTG treatment leads to reduced HIV-1 genetic and amino-acid diversification.
• These findings support the hypothesis that DTG's mechanism of action may inherently suppress viral evolution.
• The reduced diversification may explain the observed absence of emergent resistance mutations in treatment-naive individuals receiving DTG.