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High prevalence of natural polymorphisms in Gag (CA-SP1)
associated with reduced response to Bevirimat,
an HIV-1 maturation inhibitor and HIV protease inhibitors
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AIDS:
28 January 2010 - Volume 24 - Issue 3 - p 467-469
Seclen, Eduardo; Gonzalez, Maria del Mar; Corral, Angelica; de Mendoza, Carmen; Soriano, Vincent; Poveda, Eva
Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
Correspondence to Dr Eva Poveda, Department of Infectious Diseases, Hospital Carlos III, Sinesio Delgado 10, 28029 Madrid, Spain. Tel: +34 91 4532650; fax: +34 91 7336614; e-mail: evapoveda@hotmail.com.
"patients harboring two or more protease inhibitor resistance associated mutations showed a higher rate of polymorphisms at positions V370 (48.3% vs. 30.0%; P = 0.001) and T371 (45.7% vs. 8.1%; P < 0.001).....These results suggest that the activity of BVM could be compromised in patients with prior failure to protease inhibitors. The clinical relevance of this relatively high rate of gag changes influencing BVM susceptibility warrants further investigation, and baseline genotyping of the CA-SP1 region could be advised before prescription of the drug."
Abstract
Mutations H358Y, L363F/M, A364V and A366T/V confer in-vitro resistance to bevirimat. Moreover, polymorphisms at the Glutamine-Valine-Threonine (QVT) motif (369-371) have been associated with reduced bevirimat activity in vivo. The rate of these changes was assessed in 389 HIV+ patients naïve for bevirimat. QVT polymorphisms were frequent (47%), especially in non-B subtypes (93%). Conversely, only four patients (1%) harbored major bevirimat resistance mutations. Finally, specific gag changes were associated with protease inhibitor resistance mutations in subtype B viruses.
Novel antiretroviral drugs that inhibit different steps of the viral replication cycle have recently been approved for the treatment of HIV infection. This is the case for the CCR5 antagonist maraviroc and the integrase inhibitor raltegravir. The maturation inhibitor bevirimat (BVM, MPC 4326, formerly PA-457) is another experimental agent in late stages of clinical development. BVM is believed to bind the HIV gag protein, blocking its processing by the viral protease at the CA-SP1 cleavage site. As a result, defective viruses are released from the infected cell [1-3].
Recent studies have identified specific natural polymorphisms within gag associated with poor clinical response to BVM. These polymorphisms are located at positions Q369, V370 and T371, nearby the CA-SP1 junction [4-7]. A further change, V362I, has also been associated with a reduced BVM activity [8]. Furthermore, additional changes at four different amino acid residues within gag have shown to confer in-vitro resistance to BVM. These mutations (H358Y, L363F/M, A364V and A366T/V) are located in the vicinity of the CA-SP1 gag cleavage site [9].
The aim of our study was to examine the prevalence of natural polymorphisms and resistance mutations in gag associated with a reduced BMV antiviral activity. In addition, since exposure to protease inhibitors has shown to alter some positions around gag cleavage sites [10], we also evaluated the association between gag changes and drug resistance mutations at the protease.
CA-SP1 and protease sequences from 389 consecutive HIV-infected individuals naïve to BVM were analyzed. All sequences were obtained from plasma specimens sent for HIV drug resistance testing during year 2008 at a reference laboratory located in Madrid, Spain. HIV gag-pol sequences were obtained using the Viroseq HIV-1 Genotyping System (Abbott Diagnostics, Madrid, Spain). Phylogenetic analyses reported that 331 patients were infected with clade B and 58 with non-B subtypes (24 CRF02_AG, 7 G, 6 D, 4 C, 4 F1, 4 CRF01_AE, 2 A, 2 J, 2 CRF14_BG, 1 F, 1 H and 1 CRF12_BF). Overall, 56.1% of samples belonged to antiretroviral-experienced patients and 29.8% displayed two or more protease inhibitor-associated resistance mutations.
Overall, 184 (47.3%) specimens harbored polymorphisms at gag positions Q369, V370 or T371. Interestingly, and in agreement with prior studies [4], the rate of these changes was significantly higher in non-B than B subtypes (93.1% vs. 39.3%; P < 0.001) (Table 1). Significant differences were confined to codons V370 (51.7% vs. 32.6%; P = 0.007) and T371 (81.0% vs. 8.5%; P < 0.001), but not to Q369 (3.4% vs. 5.1%; P = 0.751). Our results in such a large study population confirm preliminary findings from smaller studies which have noticed natural polymorphisms associated to BVM resistance in around one-third (32-40%) of clade B viruses [4,11,12]. In non-B subtypes, the rate of these polymorphisms in our dataset reproduces the data derived from Los Alamos HIV database, in which more than 90% of non-B subtype sequences display changes at these codons [12]. No differences were found in the rate of gag polymorphisms when comparing naïve and antiretroviral-experienced patients. However, patients harboring two or more protease inhibitor resistance associated mutations showed a higher rate of polymorphisms at positions V370 (48.3% vs. 30.0%; P = 0.001) and T371 (45.7% vs. 8.1%; P < 0.001).s
Although polymorphisms at positions Q369, V370 or T371 have been associated with a poor virological response to BVM, it should be noticed that not all changes may display the same effect. For instance, it has been reported that CRF02_AG viruses, which almost always harbor a glutamine (Q) at position 371, completely retain the in-vitro susceptibility to BVM [13]. In our series, the T371Q polymorphism was found in 20 (5.1%) patients, including 12 infected with CRF02_AG viruses. There was no association with the presence of protease inhibitor resistance associated mutations. Although T371Q was more frequent in non-B than B subtypes, it should be noticed that this was mainly driven by the high prevalence of the CRF02_AG subtype in our dataset.
The V362I polymorphism was found in 45 (9.6%) of our patients, with no significant differences comparing B and non-B subtypes (11.2% vs. 13.8%, respectively), prior exposure or not to antiretroviral drugs (11.7% vs. 12.1%, respectively), or the presence or absence of two or more protease inhibitor resistance mutations (12.9% vs. 11.0%, respectively).
Apart from polymorphisms, major BMV resistance associated mutations were only found in four patients (1%), three of whom harbored L363M and one with A364V. All of them were antiretroviral-experienced patients infected with clade B viruses. Two of them did not harbor any protease inhibitor resistance associated mutation. The low prevalence of these mutations in our study is in agreement with findings from others [14].
In subtype B, gag changes associated with a reduced BVM susceptibility were associated with the presence of two or more protease inhibitor resistance associated mutations (P < 0.001). Several specific protease inhibitor resistance changes were significantly associated with single gag polymorphisms, as follows: protease L33F, K43T, I54V, T74P, I84V and L90M with gag Q369, protease M36I and K43T with gag V370, and protease I54V, G73S and I84V with gag T371. Significant relationships were also noticed for gag V362I (with protease Q58E) and gag A364V (with protease L33F, M46L and I84V). These results are in agreement with the recent recognition of a high prevalence of changes associated with reduced BVM activity in patients carrying viruses with protease inhibitor resistance mutations [15]. In non-B subtypes, gag changes were also significantly associated with the presence of two or more protease inhibitor resistance mutations (P < 0.001). However, we could not find single gag changes associated with specific protease inhibitor resistance mutations, most likely due to the limited size and virological heterogeneity of the non-B subtype study population.
In summary, polymorphisms associated with a loss of BVM susceptibility and major resistance mutations were identified in half (54.5%) of a large heterogeneous HIV+ population, including individuals infected with non-B subtypes, patients with prior failure to antiretroviral drugs, and patients with protease inhibitor resistance associated mutations. Gag polymorphisms were particularly frequent in non-B subtypes (over 90%). Interestingly, the rate of polymorphisms and major resistance mutations to BVM were not associated with prior antiretroviral exposure. However, several gag changes were significantly associated with the presence of protease inhibitor resistance associated mutations, at least in clade B viruses. These results suggest that the activity of BVM could be compromised in patients with prior failure to protease inhibitors. The clinical relevance of this relatively high rate of gag changes influencing BVM susceptibility warrants further investigation, and baseline genotyping of the CA-SP1 region could be advised before prescription of the drug.
Acknowledgements
The work was funded in part by grants from Fundacion Investigacion y Educacion en SIDA (IES), the European NEAT project, Red de Investigacion en SIDA (RIS, ISCIII-RETIC-RD06/006), and Fondo de Investigacion Sanitaria-FIS (CP08/00214; CP0610284; PI06/01826; FI09/00868).
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