Macrophages as the Achilles’ Heel of Raltegravir?
In vitro experiments show that during macrophage infection, the presence of a single primary raltegravir resistance mutation (Q148H, Q148R, N155H, or N155S) is sufficient to provide resistance to the drug comparable to that seen in viruses expressing both primary and secondary mutations in CD4+ T cells.
Could HIV resistance to drugs develop more easily in some cells? This is an interesting question raised by recent experiments reported in this month issue of Antimicrobial Agents & Chemotherapy:
Marsden MD, Avancena P, Kitchen CM, Hubbard T, Zack JA. Single Mutations in HIV Integrase Confer High-Level Resistance to Raltegravir in Primary Human Macrophages. Antimicrob Agents Chemother. 2011 May 31. [Epub ahead of print]. doi:10.1128/AAC.00566-11
It is known for some time that antiretrovirals work differently in T cells and macrophages. For example, nucleoside analog reverse transcriptase (RT) inhibitors typically work more effectively in macrophages than in T cells, whereas protease inhibitors are less effective in chronically infected macrophages than in T cells.
Raltegravir (RAL) resistance generally evolves in a stepwise process via one of several potential pathways. The mutually exclusive primary resistance mutations N155H, Q148H/R/K, and more rarely Y143R/C/H provide some resistance to RAL. These primary mutations are often associated with secondary mutations specific to each primary mutation pathway, which increase RAL resistance and may restore fitness defects caused by primary mutations. A secondary G140S mutation is most commonly associated with the Q148 pathway, and an E92Q mutation most often accompanies the N155H primary resistance mutation. Q148-pathway mutations typically produce viruses that are more resistant to RAL than N155-pathway mutations.
In the experiment, during macrophage infection the presence of a primary Q148 mutation alone provided high-level RAL resistance equivalent to that observed with the corresponding G140S+Q148H or G140S+Q148R double mutant viruses.
This is important, as macrophages are capable of recruiting nearby CD4+ T cells and efficiently transferring virus to them. This single-step pathway to high-level RAL resistance puts the macrophage compartment in the front line of RAL resistance development.
Key words: hiv macrophages, hiv reservoirs, raltegravir resistance