Human immunodeficiency virus reverse transcriptase and protease sequence database

Abstract

The HIV reverse transcriptase and protease sequence database is an on-line relational database that catalogues evolutionary and drug-related sequence variation in the human immunodeficiency virus (HIV) reverse transcriptase (RT) and protease enzymes, the molecular targets of antiretroviral therapy (http://hivdb.stanford.edu). The database contains a compilation of nearly all published HIV RT and protease sequences, including submissions to GenBank, sequences published in journal articles and sequences of HIV isolates from persons participating in clinical trials. Sequences are linked to data about the source of the sequence, the antiretroviral drug treatment history of the person from whom the sequence was obtained and the results of in vitro drug susceptibility testing. Sequence data on two new molecular targets of HIV drug therapy--gp41 (cell fusion) and integrase--will be added to the database in 2003.

Figure 1

Composite sequence alignment of HIV-1 protease, positions 1–99. This figure resulted from a query that retrieved all HIV-1 sequences in the database including those belonging to different subtypes and those obtained from treated and untreated individuals. Beneath the numbered consensus sequence is the number of isolates in the database for which sequence information at the position is available. The remaining lines in each row show the frequency of variation at each position in the database. Amino acids shown in red have a mutation rate ≥5%; those in blue have a mutation rate between 1 and 5%; and those in grey of 0.1–1%.

Figure 2

Composite sequence alignment of HIV-1 RT, positions 1–240. Although the RT enzyme has 560 positions, nearly all drug-resistance mutations are found between positions 40–240. This figure resulted from a query that retrieved all HIV-1 sequences in the database including those belonging to different subtypes and those obtained from treated and untreated individuals. Beneath the numbered consensus sequence is the number of isolates in the database for which sequence information at the position is available. The remaining lines in each row show the frequency of variation at each position in the database. Amino acids shown in red have a mutation rate ≥5%; those in blue have a mutation rate between 1 and 5%; and those in grey of 0.1–1%.

Figure 2

Composite sequence alignment of HIV-1 RT, positions 1–240. Although the RT enzyme has 560 positions, nearly all drug-resistance mutations are found between positions 40–240. This figure resulted from a query that retrieved all HIV-1 sequences in the database including those belonging to different subtypes and those obtained from treated and untreated individuals. Beneath the numbered consensus sequence is the number of isolates in the database for which sequence information at the position is available. The remaining lines in each row show the frequency of variation at each position in the database. Amino acids shown in red have a mutation rate ≥5%; those in blue have a mutation rate between 1 and 5%; and those in grey of 0.1–1%.

Figure 3

Phenotypic drug susceptibility data on about 2000 HIV-1 isolates. Drug susceptibility to each of the 16 FDA-approved drugs are shown. The first column contains the nucleoside/nucleotide RT inhibitors: 3TC (lamivudine), ABC (abacavir), AZT (zidovudine), DDC (zalcitibine), DDI (didanosine), D4T (stavudine) and TDF (tenofovir). The second column contains the nonnucleoside RT inhibitors: DLV (delavirdine), EFV (efavirenz) and NVP (nevirapine). The third column contains the protease inhibitors: APV (amprenavir), IDV (indinavir), LPV (lopinavir), NFV (nelfinavir), RTV (ritonavir) and SQV (saquinavir). Each point represents the fold decrease in susceptibility of a single virus isolate compared with the susceptibility of a wildtype control isolate (X-axis). Blue points represent results on tests with no known drug-resistance mutations. Red points represent results on tests of isolates with at least one drug-resistance mutation. The maximum number of tests shown (Y-axis) that yield the same result is 40. A large proportion of these results were obtained using one of three well-characterized recombinant virus drug susceptibility assays (–13).