Mutation N155H in HIV-2 integrase confers high phenotypic resistance to raltegravir and impairs replication capacity.
BACKGROUND
Raltegravir has been shown to be active against wildtype HIV-2 with a phenotypic susceptibility similar to HIV-1. Due to the recent introduction of these novel inhibitors, information on the selection of resistance mutations and its phenotypic effect in this population is scarce.


OBJECTIVE
To explore in vitro the effect of raltegravir resistance in one individual with HIV-2 infection who failed raltegravir-HAART.


METHODS
A 20-year-old man with HIV-2 infection received a raltegravir-based HAART regimen. Drug resistance mutations were examined in the integrase gene by sequence analysis. Phenotypic analyses were performed in two HIV-2 isolates from the patient (wildtype isolate: SP-2p2-175 and mutant isolate: SP-2p2-189) and a laboratory reference strain (HIV-2 ROD). Susceptibility to raltegravir was assessed in a PBMC culture assay. Furthermore, a replicative capacity assay was performed.


RESULTS
After introduction of raltegravir, patient's HIV-2 viremia dropped 1 log but did not reach undetectability. Genotypic analysis at month 8 with raltegravir, revealed the development of N155H resistant mutation along with other changes in the HIV-2 integrase: V72I, I84V, A153G, N160K and S163S/G. These changes resulted in a 37-fold increase in phenotypic resistance to raltegravir. Wildtype HIV-2 integrase (SP-2p2-175) had an IC(50) of 21.5nM and HIV-2 mutant virus (SP-2p2-189) showed an IC(50) of 789nM. SP-2p2-189 virus presented also lower replicative capacity in the absence of raltegravir than wildtype.


CONCLUSIONS
A continued low HIV-2 viral load seems to be enough to select the N155H mutation, which despite significantly impairing viral replication, shows a level of resistance sufficient to give a selective advantage to the virus that maintains this pathway of resistance to raltegravir overtime.
Salgado
María
M
Service of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
Toro
Carlos
C
Simón
Ainhoa
A
Garrido
Carolina
C
Blanco
Francisco
F
Soriano
Vincent
V
Rodés
Berta
B
D000595:Amino Acid Sequence; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D019427:HIV Integrase / Q000235:genetics*; D015498:HIV-2 / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011760:Pyrrolidinones / Q000494:pharmacology*; D012367:RNA, Viral / Q000097:blood; D000068898:Raltegravir Potassium; D016415:Sequence Alignment; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects*; D055815:Young Adult
D044966:Anti-Retroviral Agents; D011760:Pyrrolidinones; D012367:RNA, Viral; D000068898:Raltegravir Potassium; D019427:HIV Integrase; C514802:p31 integrase protein, Human immunodeficiency virus 2