Polymorphism and Drug-Selected Mutations in the Protease Gene of Human Immunodeficiency Virus Type 2 from Patients Living in Southern France

Abstract

The susceptibility of human immunodeficiency virus type 2 (HIV-2) to protease inhibitors (PI) is largely unknown. We studied HIV-2 protease genes from 21 HIV-2-infected patients who were exposed or not exposed to PI. The aim of this study was (i) to characterize the polymorphism of HIV-2 protease in the absence of drug, (ii) to know whether the HIV-2 protease gene naturally harbors HIV-1 drug resistance codons, and (iii) to identify mutations emerging under PI-selective pressure. Sixty-five HIV-2 RNA or proviral DNA samples were directly sequenced from the plasma or peripheral blood mononuclear cells of 8 patients who had received PI and 13 patients who had never received any antiretroviral. In untreated patients, the highest amino acid variability in HIV-2 protease was observed at positions 14, 40, 43, 46, 65 and 70, and seven codons (10V, 32I, 36I, 46I, 47V, 71V, and 73A) associated with drug resistance in HIV-1 were highly prevalent. In addition, at six positions (positions 7, 46, 62, 71, 90, and 99), the amino acid variability or the amino acid frequencies or both differed significantly in PI-treated and untreated patients, suggesting that mutations 7K3R, 46V3I, 62V3A/T, 71V3I, 90L3M and 99L3F were occurring under PI-selective pressure. At these positions, at least one sample simultaneously harbored both wild-type and mutated codons, while substitutions at positions 62, 71, 90, and 99 were confirmed in a longitudinal analysis. Moreover, the presence of codons 46I and 99F in the absence of drug in HIV-2 subtype B proteases may reflect natural resistance to PI. In conclusion, the present study revealed that HIV-2 strains harbor specific patterns of natural polymorphism and resistance.

Polymorphism of the Human Immunodeficiency Virus Type 2 (HIV-2) Protease Gene and Selection of Drug Resistance Mutations in HIV-2-Infected Patients Treated with Protease Inhibitors

“…We found also sequence variability at 8 residues corresponding to those associated with PI resistance in HIV-1. Recently two other studies reported similar results although some of the residues implicated were different (4,19); in particular, Pieniazek et al found a 30N substitution in 1 out of 75 infected patients. Here, we show that treatment-associated changes occurred in the HIV-2 PR gene at sites corresponding to some of those conferring HIV-1 PI resistance.…”

“…Only two other studies have reported natural polymorphism of the HIV-2 PR gene (4,19). We found that 47 of the 99 amino acid positions of HIV-2 PR were polymorphic, which is more than the number reported by Colson et al (4), probably due to the higher number of sequences analyzed in our study.…”

“…Only two other studies have reported natural polymorphism of the HIV-2 PR gene (4,19). We found that 47 of the 99 amino acid positions of HIV-2 PR were polymorphic, which is more than the number reported by Colson et al (4), probably due to the higher number of sequences analyzed in our study. We found that positions 14, 17, 40, 41, and 70 were highly polymorphic, in contrast to what was found for HIV-1 PR, with the exception of position 41, which has been previously described as highly polymorphic in HIV-1 (2).…”

Virological Response to Highly Active Antiretroviral Therapy in Patients Infected with Human Immunodeficiency Virus Type 2 (HIV-2) and in Patients Dually Infected with HIV-1 and HIV-2 in The Gambia and Emergence of Drug-Resistant Variants

“…naturally in all the HIV-2 samples sequenced (Table 2). Also, polymorphisms were found at positions L76V (M in HIV-2) and V82A/T/F (I in HIV-2), which are known to harbor major HIV-1 PI mutations, and at positions of minor mutations, E34Q (A in HIV-2), D60E (K in HIV-2), and L63P (E in HIV-2) (10,11,49).…”

Development and Evaluation of an Oligonucleotide Ligation Assay for Detection of Drug Resistance-Associated Mutations in the Human Immunodeficiency Virus Type 2 pol Gene

“…HIV-2 is restricted mainly to West African countries such as Senegal, Guinea Bissau, and The Gambia (29), where its prevalence varies from 1 to 10% of the adult population (11,17,21,26,31,35), although the prevalence can be as high as 28% in high-risk groups such as commercial sex workers in The Gambia (29). Cases of HIV-2 infection occur in countries outside of West Africa, such as Portugal and countries with former socioeconomic links to Portugal, including southwest India, Angola, Mozambique, and Brazil (2,27,29).…”