Amantadine Resistance

1

• Amantadine Resistance
• A. Hay
• (MRC National Institute for Medical Research,
  London)
• VIRGIL Antiviral Training Course
• London, 3-6 October 2006

2
(No Transcript)
3
(No Transcript)
4
(No Transcript)
5
(No Transcript)
6
(No Transcript)
7
(9 subtypes)
(16 subtypes)
8
(No Transcript)
9
(No Transcript)
10
(No Transcript)
11
(No Transcript)
12
Location of Ser31Asn mutation in the M2 proton
channel which causes resistance to amantadine
13
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

14
(No Transcript)
15
(No Transcript)
16
Emergence of amantadine resistance in human and
animal viruses

• Pre 1980s low incidence approx. 1
• Mid 1980s 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?)

17
Emergence of amantadine-resistant H3N2 viruses,
1994-2005
Bright et al 2005
18
(No Transcript)
19
(No Transcript)
20
(No Transcript)
21
ELISA Effect of rimantadine on expression of HA
in MDCK cells infected with rimantadine-sensitive
and rimantadine-resistant influenza A H3N2
viruses
S31N
S31N
Rim
A30V
Rim
22
Sensitivity of H5N1 Viruses to Rimantadine
Virus Inoculum Virus Growth (HA Titre at 70 hr p.i.) Virus Growth (HA Titre at 70 hr p.i.) Virus Growth (HA Titre at 70 hr p.i.) Virus Growth (HA Titre at 70 hr p.i.) Virus Growth (HA Titre at 70 hr p.i.)
Rimantadine (?M) Rimantadine (?M) Rimantadine (?M) Rimantadine (?M) 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