Abstract
The HIV genome is rich in A but not G or U and deficient in C. This nucleotide bias controls HIV phenotype by determining the highly unusual composition of all major HIV proteins. The bias is also responsible for the high frequency of narrow DNA minor groove sites in the double-stranded HIV genome as compared to cellular protein coding sequences and the bulk of the human genome. Since drugs that bind in the DNA minor groove disrupt nucleosomes on sequences that contain closely spaced oligo-A tracts which are prevalent in HIV DNA because of its bias, it was of interest to determine if these drugs exert this selective inhibitory effect on HIV chromatin. To test this possibility, nucleosomes were reconstituted onto five double-stranded DNA fragments from the HIV-1 pol gene in the presence and in the absence of several minor groove binding drugs (MGBDs). The results demonstrated that the MGBDs inhibited the assembly of nucleosomes onto all of the HIV-1 segments in a manner that was proportional to the A-bias, but had no detectable effect on the formation of nucleosomes on control cloned fragments or genomic DNA from chicken and human. Nucleosomes preassembled onto HIV DNA were also preferentially destabilized by the drugs as evidenced by enhanced nuclease accessibility in physiological ionic strength and by the preferential loss of the histone octamer in hyper-physiological salt solutions. The drugs also selectively disrupted HIV-containing nucleosomes in yeast as revealed by enhanced nuclease accessibility of the in vivo assembled HIV chromatin and reductions in superhelical densities of plasmid chromatin containing HIV sequences. A comparison of these results to the density of A-tracts in the HIV genome indicates that a large fraction of the nucleosomes that make up HIV chromatin should be preferred in vitro targets for the MGBDs. These results show that the MGBDs preferentially disrupt HIV-1 chromatin in vitro and in vivo and raise the possibility that non-toxic derivatives of certain MGBDs might serve as a novel class of anti-HIV agents.
Highlights
The tremendous genetic variation of HIV-1 is responsible for the appearance of drug and antibody resistant forms of HIV-1 that appear during infection, and this genetic swarm is a major obstacle to the treatment of AIDS and to the development of an HIV vaccine
A comparison of these results to the density of A-tracts in the HIV genome indicates that a large fraction of the nucleosomes that make up HIV chromatin should be preferred in vitro targets for the minor groove binding drugs (MGBDs). These results show that the MGBDs preferentially disrupt HIV-1 chromatin in vitro and in vivo and raise the possibility that non-toxic derivatives of certain MGBDs might serve as a novel class of antiHIV agents
Pentamidine has been used to prevent and treat opportunistic pneumonia that is caused by Pneumocystis carinii which is common in AIDS patients
Summary
The tremendous genetic variation of HIV-1 is responsible for the appearance of drug and antibody resistant forms of HIV-1 that appear during infection, and this genetic swarm is a major obstacle to the treatment of AIDS and to the development of an HIV vaccine. Substantial progress has been made during the past three decades in the development of antiHIV drugs which has culminated in the use of combination antiviral drug therapy for treatment of viremia, HIV-drug-resistant mutants have been found for all nucleoside analogs and nonnucleoside and protease inhibitors used in the treatment of HIV-infected individuals. The major challenge in current HIV research is the development of methods to eliminate the replication competent provirus that has integrated as a double stranded DNA molecule within the host cell chromatin. This viral reservoir is resistant to the host’s immune system and is resistant to the current drugs used to treat viremia. Little progress has been made during the past to eliminate or inactivate the replication competent provirus and there is no universal agreement as to the best strategies that should be used to approach the problem in the future [5,6]
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