Natural polymorphism in protease and reverse transcriptase genes and in vitro antiretroviral drug susceptibilities of non-B HIV-1 strains from treatment-naive patients.
BACKGROUND
Most studies on antiretroviral (ARV) resistance of human immunodeficiency virus (HIV) have been done on subtype B which only represent a limited proportion of infections worldwide.


OBJECTIVE
Understand baseline susceptibilities to ARVs in non-B strains.


METHODS
To explore in greater detail possible intrinsic resistance to antiretroviral drugs in non-B subtypes, phenotypic resistance was tested in 35 non-B (A, D, F, G, J; CRF02, 06, 09, 11, 13) HIV-1 isolates obtained from ARV treatment naive patients. The panel includes strains with an increasing number of minor mutations in the protease gene and/or with atypical mutations at positions associated with resistance in protease and RT.


RESULTS
We detected phenotypic resistance (fold-change values equal or superior to biological test cut-offs (BCO) in 14 of the 35 strains, 4 strains had decreased in vitro susceptibility to more than one drug. However, it is important to note that in most cases the increased fold-changes were close to the BCOs. Phenotypic resistance was observed against each of the three ARV drug classes: ritonavir (n=3), nelfinavir (n=2), saquinavir (n=2), zidovudine (n=2), stavudine (n=1), didanosine (n=1); delavirdine (n=6), efavirenz (n=1) and nevirapine (n=1). Some mutations could be associated with decreased in vitro susceptibility: 1 of 3 strains only with mutations M46I/L in protease, 1/2 A98S, K101N, V108I, V179I, and P236L in reverse transcriptase. Interestingly, the presence of an increasing number of minor mutations in the protease gene was not associated with decreased in vitro susceptibility to protease inhibitors.


CONCLUSIONS
It is necessary to continue phenotypic studies on non-subtype B strains to identify the role of all polymorphisms present in protease and RT genes and to optimize interpretation algorithms. Data obtained from large, diverse populations of HIV-1 infected individuals is critical for defining and standardizing the quantification of resistance (phenotypic and genotypic testing).
UMR145, IRD (Institut de Recherche pour le Développement) and University of Montpellier, 911 Avenue Agropolis, BP 64501, 34394 Montpellier Cedex 01, France.
Laurence
L
Vergne
Lieven
L
Stuyver
Margriet
M
Van Houtte
Christelle
C
Butel
Eric
E
Delaporte
Martine
M
Peeters
D000465:Algorithms; D024882:Drug Resistance, Viral / Q000235:genetics; D005814:Genes, Viral; D016333:HIV Protease / Q000235:genetics*; D015497:HIV-1 / Q000145:classification / Q000201:enzymology* / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D009154:Mutation; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012367:RNA, Viral / Q000097:blood; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D012367:RNA, Viral; D012194:RNA-Directed DNA Polymerase; D016333:HIV Protease