Amantadine Resistance

A. Hay(MRC National Institute for Medical Research, London)

VIRGIL Antiviral Training CourseLondon, 3-6 October 2006

(9 subtypes)

(16 subtypes)

a

N MRI

a

N MRI

Location of Ser31Asn mutation in the M2 proton channel which causes resistance to amantadine

Amantadine/Rimantadine resistant mutants

• Mutations in M2 Channel pore; residues 26,27,30,31,34

• Emerge frequently in vitro and in vivo(30% or higher)

• Similar to wt in infectivity, virulence and transmissibility

Emergence of amantadine resistance in human and animal viruses

• Pre 1980’s – low incidence; approx. 1%• Mid 1980’s – European swine viruses

(sporadic human cases)• 2000 - - avian H5N1,H9N2 (SE Asia)• 2003 - - avian H5N1; (Z,clade 1); human cases

H5N3(SE Asia)

H7N2(N America)• 2003 - - human H3N2 (China/Hong Kong; worldwide?)

Emergence of amantadine-resistant H3N2 viruses, 1994-2005

Bright et al 2005

ELISA: Effect of rimantadine on expression of HA in MDCK cells infected with rimantadine-sensitive and rimantadine-

resistant influenza A H3N2 viruses

S31NS31N

A30V

+Rim

+Rim

Virus Inoculum Virus Growth (HA Titre at 70 hr p.i.)

Rimantadine (M)

0 0.05 0.5 5.0 50

A/HK/156/97 10-2 128 256 32 8 4

(Sensitive) 10-3 128 128 16 4 2

A/Vietnam/1194/04 10-2 128 128 128 128 128

(Resistant) 10-3 128 64 64 64 64

A/Indonesia/5/05 10-2 1024 256 256 32 16

(Sensitive) 10-3 1024 256 128 32 8

A/Indonesia/6/05 10-2 512 256 256 256 256

(Resistant) 10-3 256 256 256 256 256

Ty/Turkey/1/05 10-2 64 64 16 8 8

(Sensitive) 10-3 64 64 16 4 4

Sensitivity of H5N1 Viruses to Rimantadine