Y181C

Y181C is a substitution of tyrosine (Y) with cysteine (C) at residue 181 of the HIV-1 reverse transcriptase (RT) enzyme. It is one of the non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations and resides within the NNRTI-binding pocket of RT. The change alters the pocket's shape and chemical properties, reducing drug binding and enabling continued viral replication in the presence of NNRTIs.

In terms of drug susceptibility, Y181C confers high-level resistance to several NNRTIs, most notably nevirapine and delavirdine. It also contributes to reduced susceptibility to efavirenz, with the exact impact influenced by the viral genetic background and the presence of additional mutations. The mutation can further affect other NNRTIs such as rilpivirine and etravirine when combined with other resistance substitutions, reflecting the cross-resistance pattern within the NNRTI class.

Clinically, Y181C often emerges under selective pressure from NNRTI-containing antiretroviral regimens and is associated with virologic failure on those therapies. It can be detected through genotypic resistance testing and may be observed as a transmitted resistance mutation in treatment-naive individuals. When Y181C is present, NNRTI options for subsequent therapy may be limited, frequently guiding clinicians toward regimens based on non-NNRTI classes, such as boosted protease inhibitors or integrase inhibitors.

Biologically, Y181C can impact the fitness of HIV-1, sometimes incurring a modest replication cost that may be offset by other mutations. The mutation can persist in the viral population even after NNRTI selective pressure is removed, contributing to longer-term resistance patterns and influencing future treatment choice.