Replicative cycle of HIV-1 and Therapy

Entry

Reverse Transcription

Integration

Maturation

Polymerase and RNase H active sites of HIV-1 RT

17-18 bp

p51

p66

p66

p51

DNAn+1DNAn

dNTP PPi

DNAn+2 ...

dNTP PPi

DNA synthesis

N

C

H

3

N

O

N

N

Cl

N

O

O

F

3

C

H

Nevirapine

Efavirenz

Structures of NON-nucleoside analogue RT inhibitors (NNRTIs)

HIV-1 RT Bound to a Non-Nucleoside RT Inhibitor(NNRTI)

Active site

Nevirapine

HIV-1 RT Bound to a NNRTI + Surrounding NNRTI-associated Drug Resistance Mutations

Active site

Nevirapine

Drug resistance mutations

N

H

O

C

H

3

O

N

O

Ho

O

H

Thymidine

N

H

O

C

H

3

O

N

O

Ho

N

3

N

H

O

C

H

3

O

N

O

Ho

O

N

N

H

2

N

O

Ho

O

H

Cytidine

O

N

N

H

2

N

O

S

Ho

AZT d4T

3TC

Structures of nucleoside analogue RT inhibitors (NRTIs)

HIV-1 RT: Active Site and NucleosideAnalog Drug Resistance Mutations

Active site

Incoming nucleotide

Drug resistance mutations

HIV-1 Protease Bound to an Inhibitor

Substrate Cleft:

Active site:

Indinavir

HIV-1 Protease Bound to Inhibitor + Drug Resistance Mutations

Substrate Cleft:

Active site:

Indinavir

“Major” mutations

“Minor” mutations