PubMed · 9872292
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1998-12-17. Setting a bad example on AIDS.. https://doi.org/10.1038/25174
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Within the past few years encouraging progress has been made in the treatment of HIV-1 infection, largely due to the combined use of HIV-1 protease inhibitors with nucleoside and non-nucleoside reverse transcriptase inhibitors. Despite this, HIV-1 infection is still a major global problem and the emergence of a drug resistant virus is ever present. There is a continuing need to develop new therapeutic strategies as well as improve upon all forms of existing therapies for the treatment of this viral infection. It has now been almost a decade since the first demonstration that ribozymes can effectively inhibit HIV-1 infectious spread in cell culture. Since then, ribozymes have progressed into human clinical trials primarily through gene therapy approaches. This progression brings ribozymes into the forefront as an important addition to the growing arsenal of anti-HIV-1 weapons. The following review covers the developments in anti-HIV-1 ribozyme usage over the past decade and summarizes the current state of ribozyme development for the purpose of inhibiting HIV-1 infection.
We have determined the sequence of the human immunodeficiency virus type 1 (HIV-1) vif genes from a cohort of 42 long-term nonprogressors (LTNP) and compared these sequences to those of 8 late progressors. The coding potential of the vif open reading frame directly derived by nested PCR from uncultured peripheral blood mononuclear cell DNA was conserved in all 50 individuals. The nucleotide distances between vif sequences were not significantly different between LTNP and late progressors, indicating similar selections of viruses within both types of long-term HIV-1-infected subjects. However, a statistically significant correlation between an amino acid signature at position 132 of Vif and the viral load was found within LTNP. Namely, amino acid Ser was associated with low viral load and amino acid Arg with high viral load. This signature was also observed when LTNP with low viral load were compared to progressors. The Ser132 signature was introduced in place of Arg132 present in the HIV-1 YU-2 Vif prototype into chimeric viruses to assess the impact of Vif signature on the virus. While the replication properties in the SupT1 cell line were unmodified, the mutagenized virus revealed a fivefold decreased replication in activated PBMC, suggesting a possible role of this Vif signature for viral production in vivo.
Preliminary preclinical and clinical data suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) may decrease viral replication. Therefore, 105 individuals with AIDS who were receiving nucleoside analogue therapy were enrolled in a placebo-controlled, double-blind study and were randomized to receive either 125 microgram/m(2) of yeast-derived, GM-CSF (sargramostim) or placebo subcutaneously twice weekly for 6 months. Subjects were evaluated for toxicity and disease progression. A significant decrease in mean virus load (VL) was observed for the GM-CSF treatment group at 6 months (-0.07 log(10) vs. -0.60 log(10); P=.02). More subjects achieved human immunodeficiency virus (HIV)-RNA levels <500 copies/mL at >/=2 evaluations (2% on placebo vs. 11% on GM-CSF; P=.04). Genotypic analysis of 46 subjects demonstrated a lower frequency of zidovudine-resistant mutations among those receiving GM-CSF (80% vs. 50%; P=.04). No difference was observed in the incidence of opportunistic infections (OIs) through 6 months or survival, despite a higher risk for OI among GM-CSF recipients. GM-CSF reduced VL and limited the evolution of zidovudine-resistant genotypes, potentially providing adjunctive therapy in HIV disease.