Abstract
Since the antiretroviral therapy (ART) was introduced to patients infected by human immunodeficiency virus (HIV), the HIV related mortality and morbidity have been significantly reduced. The major obstacle for long-term successful anti-HIV treatment is the emergence of drug resistant mutants. Current data of drug resistance was mainly obtained on HIV-1 subtype B but rarely on non-B virus, even more rare with newly emerged circulating recombinant forms (CRFs). The lack of such data limits the rational management of ART for the increasing number of patients infected by non-subtype B virus. In this study, a HIV-1 CRF07_BC strain CNGZD was isolated from a HIV patient and its genome was sequenced and deposited in GenBank (JQ423923). Potential drug resistant mutants of this CRF07_BC virus strain were selected in PBMCs cultures in the presence of Nevirapine (NVP), which is the most frequently used antiretroviral drug in China. Four combination profiles of mutations were identified in the NVP-selected mutants, which were initiated with A98G, V108I, Y181C and I135T/I382L and followed by more than two other mutations at the end of the selections, respectively. A total of seven previously reported mutations (A98G, V106M, V108I, I135T, Y181C, V189I, K238N) and seven novel mutations (P4H, T48I, I178M, V314A, I382L/V, T386A) in the reverse transcriptase gene were found in these NVP-selected mutants. Phenotypic analysis in the NVP-selected mutants showed that all the mutations, except P4H, contribute to NVP resistance. Among them, V106M and Y181C reduce NVP susceptibility for more than 20-fold, while the other mutations cause less than 20 folds drug resistance. Although the information obtained in this in vitro selection study may not fully cover resistant mutations which will actually occur in patients, it has still provided useful information for rational management of ART in patients infected with HIV CRF_BC subtype.
Highlights
Circulating recombinant forms (CRFs) are the virus with recombinant genomes from different subtypes, which have been detected as epidemic strains and displayed as their identifying numbers and with letters presenting the involved subtypes [1]
The results of subtyping analysis showed that CNGZD belonged to human immunodeficiency virus (HIV)-1 CRF07_BC as determined in both phylogenetic and bootscanning methods using Rega HIV-1 subtyping tool (Figure 1)
For CNGZD and CRF07_BC reference strain 97CN54, five segments from subtype B were found in subtype C backbone and the recombination points located in similar positions at p17/p24, p7/p6, reverse transcriptase (RT), Vpr/ Vpu, nef regions (Figure 2)
Summary
Circulating recombinant forms (CRFs) are the virus with recombinant genomes from different subtypes, which have been detected as epidemic strains and displayed as their identifying numbers and with letters presenting the involved subtypes [1]. Nevirapine (NVP), the first generation of nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI), is widely used with nucleoside RT inhibitor (NRTI) as the first line antiretroviral regimens, while NVP-containing highly active antiretroviral therapy (HAART) is the most popular drug combination in China [7]. Genetic diversity in different subtypes or CRFs may affect the drug resistance development in patients [9]. The limited information for potential drug resistance of CRF07_BC was based on the investigation in treatment naıve patients but not from treatment failure patients [5]. To improve managements of NVP-containing antiretroviral therapy for these patients, it is urgent to know the NVP resistant mutation profiles in CRF07_BC. In the current studies based on treatment failure patients, drug-resistance cannot be diagnosed before the treatment failure, which always needs several years
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