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Gag
Mutations Identified in Wild-type HIV-1 that Impact Viral Replication
Capacity (RC) May Represent Cytotoxic T-Lymphocyte (CTL) Escape
Mutations
N Parkin, C Chappey, E Lam, and C Petropoulos
ViroLogic, Inc, South San Francisco, CA
The majority of clinical samples submitted
for phenotypic and genotypic resistance testing that demonstrate
reduced protease inhibitor (PI) susceptibility also have one or
more “primary” PI-selected resistance-associated
mutations (RAMs). However, occasionally samples are
observed with unexplained PI resistance.
Primary PI RAMs were defined as any
change vs. wild-type at positions 23, 24, 30, 32, 46, 47, 48, 50,
54, 82, 84, 88, 90, with the following exceptions: I54V and N88D
(not reported to occur without other primary mutations) and V82I
(known polymorphism in PI-naïve patients).
PI susceptibility (fold-change [FC]
in IC50), gag (positions 418-500) and PR genotype were determined
with the PhenoSense
and GeneSeq assay, respectively (ViroLogic, Inc.).
Fisher’s exact test was used to determine
genotypic changes in gag or PR associated with reduced PI susceptibility;
mixtures were counted as mutant, and variables with p<0.005 were
considered significant.
Results
A small group of samples with no primary
PI RAMs but at least one PI with FC > 5 was identified (n=125;
0.5% of samples lacking PI RAMs); 28 had at least one PI with FC
> 10. The median/maximum FC to amprenavir, indinavir, nelfinavir,
ritonavir, saquinavir, lopinavir, and atazanavir were 2.4/25, 3.1/15,
9.6/65, 5.2/75, 2.7/52, 2.4/28, and 3.6/41, respectively.
The
number of samples with FC > 5 to 1, 2, 3, or ≥4 PIs was
89 (mostly nelfinavir), 17 (mostly nelfinavir and ritonavir), 11,
and 8, respectively. Compared to 3956 samples with no PI RAMs and
all PIs FC < 5, PR mutations over-represented in samples with
at least one PI FC > 5 included: L10IV, I13V, L19V, K20IMT, A22V,
M36IV, N37D, I54V, H69R, A71ITV, G73S, T74KS, V82I, N83D, N88D and
I93L. In gag, several changes including K418ER, A431V, I437V, L449IP,
P453L, and E482G were associated with PI FC >5.
Conclusions
Although rare, reduced susceptibility
to PIs in excess of 5-fold in the absence of primary mutations in
PR can be observed in clinical samples. Accumulation of secondary
mutations and/or polymorphisms in PR, as well as changes in the
C-terminal region of gag, are potential contributors to reduced
PI susceptibility and may modulate response to PI treatment.
06/27/05
Reference
N Parkin and others. Reduced Susceptibility
to Protease Inhibitors (PI) in the Absence of Primary PI Resistance-Associated
Mutations. Abstract 108. XIV International Drug Resistance Workshop.
June 7-10, 2005. Quebec City, Quebec, Canada. [Antiviral
Therapy 2005; 10:S118]
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