polGene Sequence Variation in Swedish HIV-2 Patients Failing Antiretroviral Therapy

Abstract

There is limited knowledge about how to treat and interpret results from genotypic resistance assays in HIV-2 infection. Here, genetic variation in HIV-2 pol gene was studied in 20 of 23 known HIV-2 cases in Sweden. Five patients with signs of virological treatment failure were longitudinally studied. Clinical, virological and immunological data were collected and the protease (PR) and first half of the reverse transcriptase (RT) was amplified and directly sequenced from plasma samples. Moderate to extensive genetic evolution was observed in four of the five patients who failed treatment. Some mutations occurred at positions known to confer resistance in HIV-1, but many occurred at other positions in PR and RT. All patients had been treated with zidovudine alone or in combination with other antiretroviral drugs, but none displayed a mutation at position 215, which is the primary zidovudine resistance site in HIV-1. Instead, a E219D mutation evolved in virus from two patients and a Q151M mutation evolved in two other patients. A M184V mutation indicative of lamivudine resistance was detected in three patients. The virus of one patient who had been treated with ritonavir, nelfinavir, and lopinavir successively acquired nine unusual mutations in the protease gene, most of which are not considered primary or secondary resistance mutations in HIV-1. Our data indicate that the evolutionary pathways that lead to antiretroviral resistance in HIV-2 and HIV-1 exhibit both similarities and differences. Genotypic HIV-2 resistance assays cannot be interpreted using algorithms developed for HIV-1, instead new algorithms specific for HIV-2 have to be developed.

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

“…Apart from the ZDV-associated secondary mutations V75I and K219Q/E, present as natural polymorphisms, other ZDV mutations have not been found in any of the patients. As previously observed, accumulation of the six thymidine analogue resistance mutations, M41L, D67N, K70R, L210W, T215Y, and K219Q/E (32), marking classic ZDV resistance in HIV-1 (1,6,9,23,49), was also absent in the HIV-2 sequences. Therefore, we conclude that high-level resistance to 3TC also contributed to the virological failure observed for patients 2 and 11 and that the viruses in these patients either are sensitive to ZDV or have as yet unidentified ZDV-associated mutations.…”

“…Generally, fewer mutations accumulated in these HIV-2 patients with viral rebound than in those from previous studies (1,6,9,23), and the Q151M mutation was absent. This finding indicates that efficient therapy results in fewer mutations and therefore less cross-resistance to other drugs.…”

Thymidine Analogue Resistance Suppression by V75I of HIV-1 Reverse Transcriptase

“…Wild-type HIV-2 RT contains Ser instead of Thr at position 215, and only one nucleotide change is needed to obtain the substitution S215Y. However, Q151M emerges as the major AZT resistance mutation in HIV-2 RT, whereas TAMs are relatively uncommon in HIV-2-infected patients (72)(73)(74). Molecular modeling studies suggested that several amino acid differences around the putative ATP binding site of HIV-2 RT in comparison with the HIV-1 RT could account for these differences (75).…”

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

“…The 26 samples from The Netherlands were from 16 treatment-experienced HIV-2-infected patients, mostly of West African origin, who were genotyped at the Erasmus Medical Centre in Rotterdam, The Netherlands. The 30 Swedish samples were from 12 patients-6 untreated, 1 treated successfully, and 5 failing therapy-as previously described (8). These samples were selected from 20 of 23 known cases of HIV-2 in Sweden.…”

“…These samples were selected from 20 of 23 known cases of HIV-2 in Sweden. Most of these patients were immigrants from different West African countries (8).…”