Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.16 (HIV-1 protease)
 2,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epitopes in HIV polymerase were analyzed by peptide binding to human leukocyte antigen (HLA) A0201 molecules, the most frequent HLA class in the Caucasian population. We found that HIV-1 protease peptides representing both the wild type and anticipated drug resistance variants of the sequence bound well to HLA-A0201. We also found that wild type as well as a double mutated variant of the epitope was strongly immunogenic in HLA-A0201 transgenic mice, either as individual peptides or encoded in DNA multi-CTL epitope constructs. Immunological cross-reactivity between different variants of the peptide could be seen, suggesting that it may be possible to induce a broad immune response by immunizing with drug resistance-mutated epitopes. This may be of advantage for HIV-1 infected patients since such a response may cause a better outcome of an anti-retroviral drug therapy.
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PMID:Immunological cross-reactivity against a drug mutated HIV-1 protease epitope after DNA multi-CTL epitope construct immunization. 1618 10

Human immunodeficiency virus (HIV-1) is, like most pathogens, under selective pressure to escape the immune system of its host. In particular, HIV-1 can avoid recognition by cytotoxic T lymphocytes (CTLs) by altering the binding affinity of viral peptides to human leukocyte antigen (HLA) molecules, the role of which is to present those peptides to the immune system. It is generally assumed that HLA escape mutations carry a replicative fitness cost, but these costs have not been quantified. In this study, we assess the replicative cost of mutations which are likely to escape presentation by HLA molecules in the region of HIV-1 protease and reverse transcriptase. Specifically, we combine computational approaches for prediction of in vitro replicative fitness and peptide binding affinity to HLA molecules. We find that mutations which impair binding to HLA-A molecules tend to have lower in vitro replicative fitness than mutations which do not impair binding to HLA-A molecules, suggesting that HLA-A escape mutations carry higher fitness costs than non-escape mutations. We argue that the association between fitness and HLA-A binding impairment is probably due to an intrinsic cost of escape from HLA-A molecules, and these costs are particularly strong for HLA-A alleles associated with efficient virus control. Counter-intuitively, we do not observe a significant effect in the case of HLA-B, but, as discussed, this does not argue against the relevance of HLA-B in virus control. Overall, this article points to the intriguing possibility that HLA-A molecules preferentially target more conserved regions of HIV-1, emphasizing the importance of HLA-A genes in the evolution of HIV-1 and RNA viruses in general.
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PMID:Estimating the fitness cost of escape from HLA presentation in HIV-1 protease and reverse transcriptase. 2265 56