Synergistic inhibition of AZT-resistant HIV by AZT combined with poly(I):poly(C12U), without synergistic toxicity to bone marrow progenitor cell elements.
Mutation of human immunodeficiency virus (HIV) to drug resistance is an obstacle to HIV containment, and may account for the transitory nature of the improvement in CD4 cell counts of patients receiving azidothymidine (AZT). The emergence of AZT-resistant (AZTR) virus might be suppressed if a second therapeutic could be added; however, such a regimen would have to confer not only additional control over HIV replication but also no additional toxicity, especially to bone marrow progenitor cells. In the present study, HIV was isolated from patients receiving AZT alone and was studied for sensitivity to the mismatched double-stranded RNA, poly(I):poly(C12U) (ampligen). In addition, the combination of poly(I):poly(C12U) plus AZT was studied in vitro for toxicity to bone marrow CFU-GM and in patients receiving combined therapy for bone marrow toxicity. HIV isolated from patients receiving AZT alone showed higher resistance to AZT than wildtype virus, but remained sensitive to poly(I):poly(C12U). Poly(I):poly(C12U) and AZT were synergistic in inhibiting all isolates of HIV tested, regardless of their AZTR phenotype. Furthermore, the combination of poly(I):poly(C12U) and AZT showed no toxicity in vitro to bone marrow CFU-GM compared to AZT alone. In 11 HIV infected individuals receiving the combinational regimen, bone marrow function gradually improved. These results indicate that poly(I):poly(C12U) was active against AZTR HIV, synergistic with AZT and did not convey added toxicity.
Gillespie
D
D
Department of Neoplastic Diseases, Hahnemann University, Philadelphia, PA 19102.
Hubbell
H R
HR
Carter
W A
WA
Midgette
P
P
Elsasser
W
W
Mullaney
R
R
Strayer
D R
DR
D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003114:Colony-Forming Units Assay; D004351:Drug Resistance; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006678:HIV / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D011070:Poly I-C / Q000009:adverse effects / Q000627:therapeutic use*; D011072:Poly U / Q000009:adverse effects / Q000627:therapeutic use*; D012330:RNA, Double-Stranded; D015215:Zidovudine / Q000009:adverse effects / Q000627:therapeutic use*
D000998:Antiviral Agents; D012330:RNA, Double-Stranded; D011072:Poly U; D015215:Zidovudine; C047490:poly(I).poly(c12,U); D011070:Poly I-C