Case Report of a Novel Amino Acid Deletion in Codon 67 and T69G Substitution in the Reverse Transcriptase of HIV-1

Abstract

Significant progress has been made in the management of infection with HIV-1 since highly active antiretroviral therapies (HAART) were widely implemented. Nevertheless, in a growing number of patients, the effectiveness of these treatments is challenged by the emergence of viral variants of decreased susceptibility to antiretroviral agents, which leads to treatment failure [1,2]. In these cases, HIV-1 drug resistance testing provides helpful information in guiding the choice of a new regimen for patients experiencing treatment failure [3,4]. Although a large number of mutations in protease and reverse transcriptase (RT) genes (including codon insertions) have been shown to correlate with drug resistance, additional efforts are required to find mutational patterns associated with resistance [5]. In this letter we describe a rare pattern of mutations in the HIV RT gene that includes a deletion of codon 67, which to our knowledge has only been reported once before [6]. The patient is a 40-year-old woman who has been HIV-positive for 15 years, and has a long treatment history. With a diagnosis of oral hairy leukoplakia, molluscum contagiosum and varicella zoster virus in 1995, she started therapy with zidovudine and lamivudine, and nelfinavir was added 10 months later. Nine months later, the patient suffered a rise in HIV-1 viral load and a drop in CD4 cell count, and therapy was shifted to efavirenz/nelfinavir/saquinavir (a combination now recognized as ineffective). Treatment was changed again 3 months later to didanosine/ stavudine/lamivudine/hydroxyurea, after a new relapse in viral load. By March 1999, a genotypic resistance assay was performed. Both protease and RT genes were amplified from plasma HIV-RNA by RT–PCR, and sequenced using an ABI 377 automated sequencer. The following pattern was found: in the protease gene, L10I, M36I, I54V, A71V, V82A and L90M; in the RT gene, M41L, K70R, T215F, K219E, K103N, Y181C and G190A. As a result of this, amprenavir was added to the drug regimen. One year later, after a further rise in the viral load, another genotypic resistance test was performed. The results indicated not only the apparition of three new resistance-associated mutations in the HIV protease gene (K20R, L63H and I84V) but also the absence of a previously detected mutation (M36I). Interestingly, two novel abnormalities had appeared in the RT gene: a deletion of the codon 67, concomitantly with the mutations T69G and A98G, in addition to the zidovudine resistance-associated mutations