Immunogenicity of Mutations Induced by Nucleoside Reverse Transcriptase Inhibitors for Human Immunodeficiency Virus Type 1-Specific Cytotoxic T Cells

Abstract

The impact of drug resistance mutations induced by nucleoside reverse transcriptase (RT) inhibitors (NRTI) on cytotoxic T-lymphocyte (CTL) recognition of human immunodeficiency virus type 1 strain LAI (HIV-1 LAI )RT was addressed in 35 treated or untreated patients. Two HIV-1 LAI RT regions encompassing mutation M41L, L74V, M184V, and T215Y/F were recognized in 75 and 83% mutated and in 33 and 42% unmutated samples, respectively. A total of 41 new CTL epitopes overlapping these mutations were predicted. Mutations enhanced HLA-binding scores of 17 epitopes, decreased scores of 5, and had no effect in 19. Four predicted epitopes containing mutations 41, 74, and 184 were tested and recognized by CD8 cells from mutated or unmutated samples, with frequencies up to 270 gamma interferon spot-forming cells per 10 6 peripheral blood mononuclear cells. Therefore, RT mutations induced by NRTI can increase the immunogenicity of RT for CTL and might allow a better immune control of resistant viruses in vivo, suggesting that specific immune therapy might help prevent these mutations.Cytotoxic T lymphocytes (CTL) specific for human immunodeficiency virus (HIV) or simian immunodeficiency virus are considered the most efficient virus-specific immune responses (4,26,29,39). The strength and the diversity of CTL responses (16, 54) have been proposed, together with reverse transcriptase (RT) infidelity (7,33,37), as an important factor for virus variability at time of asymptomatic disease and strong immune functions. Some viral mutations can decrease immunogenicity by interfering with the intracellular processing or with the HLA binding of viral peptides, thereby resulting in a lack of CTL recognition (5,11,13,14,22,30,32,34). In contrast, new HIV variants that do not interfere with such processes can be immunogenic for specific new CTL clones (16), a fact which contributes to some extent to determining HIV variability (54).The high level of HIV type 1 (HIV-1) RT sequence conservation among different HIV isolates (25) makes RT one of the most frequent targets for CTL recognition; indeed, 80% of HIV-infected individuals have specific RT-specific CTL (17). Prolonged antiviral mono-or bitherapy with nucleoside RT inhibitors (NRTI), however, results in selection of HIV-1 strains containing mutations in the RT gene (36). These mutations often have an impact on the enzymatic activity of RT and on the fitness of the virus (2, 45). These drug-induced mutations are highly standardized and characteristic of the various NRTI used (28, 38). Highly active antiretroviral therapies (HAART) combining various drug regimens have decreased the occurrence of such mutations by reducing levels of virus replication, but they concomitantly decrease the intensity of the HIV-specific CTL responses (10,15,29). Currently viral replication is efficiently controlled in only 50% of patients receiving HAART; frequency of treatment failures is increasing and correlates with high levels of drug-induced mutations (56). In industrialized countries, approximately 15% ...

Dual Selection Pressure by Drugs and HLA Class I-Restricted Immune Responses on Human Immunodeficiency Virus Type 1 Protease

“…Over the past years, some studies have provided evidence that selection pressure exerted by CTL can interfere with the development of drug resistance mutations (4,16,36,38). Drug-targeted enzymes like the viral PR are exposed to both pharmacological selection pressure and immune response selection exerted by ϩ -T-cell responses on the development of drug mutations or drug-associated polymorphisms in the PR, we analyzed PR sequences from 94 HLA class I-typed HIV-1-positive individuals.…”

Novel Cytotoxic T-Lymphocyte Escape Mutation by a Three-Amino-Acid Insertion in the Human Immunodeficiency Virus Type 1 p6 Pol and p6 Gag Late Domain Associated with Drug Resistance

“…In HIV patients treated with NRTI, the insertion frequency was 21.2% (35) to 36.4% (17) of viral sequences analyzed in these studies. Various effects of drug resistance mutations on T-cell immunity in HIV-1 infection have been reported (19,39,41), but none on the Pol NL8 epitope and by the STP/APP insertion. When Peters and colleagues inserted the coding sequences of the SPT/APP repeat into HIV-1 NL4-3, the resulting virus exhibited increased resistance to NRTI and increased reverse transcriptase content in the virion, and activity was elevated in the mutant virus, but there was a delay in Gag cleavage and viral particle release (35).…”

Reverse Transcriptase Mutations in HIV-1 Infected Patients Treated with Two Nucleoside Analogues: The Smart Study

“…One possible explanation for the poor correlation between baseline RT mutations and clinical failure over one year of follow-up might thus be the reduced fitness of variants. Furthermore, variants bearing RT mutations are better recognized by cytotoxic T-lymphocytes (38). Therefore, a better immune control ofNRTI resistant HIV -1 variants might be hypothesized.…”