Comparative analysis of anti-human immunodeficiency virus type 1 activities of dideoxynucleoside analogs in resting and activated peripheral blood mononuclear cells

Abstract

We determined the anti-human immunodeficiency virus type 1 (anti-HIV-1) activities of various dideoxynucleoside analogs by using phytohemagglutinin-activated peripheral blood mononuclear cells (PHA-PBMs) and resting PBMs (R-PBMs) as target cells. The comparative order of anti-HIV-1 activity in PHA-PBMs was azidothymidine (AZT) > dideoxycytidine (ddC) > dideoxythymidinene (d4T) > dideoxyinosine (ddI) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) > 2-␤-fluoro-dideoxyadenosine (F-ara-ddA), while that in R-PBMs was ddC > ddI, PMEA, and F-ara-ddA, >> AZT and d4T. A pronucleotide, bis-(S-acetylthioethanol)phosphotriester-ddAMP, which bypasses the anabolic monophosphorylation step for the intracellular delivery of ddAMP, was highly active both in PHA-PBMs and R-PBMs. These data may have basic and clinical relevance in the design of anti-HIV chemotherapy, particularly combination chemotherapy with dideoxynucleosides, and in the development of active pronucleotides.

Selective inhibition of syncytium-inducing and nonsyncytium-inducing HIV-1 variants in individuals receiving didanosine or zidovudine, respectively.

“…The combination of ZDV and ddI then covers both cell types and thereby inhibits both phenotypic variants. Protease inhibitors, which do not require intracellular phosphorylation, are as active in quiescent as in activated cells (53). In agreement with our model, we observed an equal inhibition of NSI and SI HIV-1 populations in individuals receiving the protease inhibitor ritonavir.…”

“…From this latter group the cytidine analogs (ddC, 3TC), but not the purine analog ddI, are even more phosphorylated in activated cells (51). The enhanced phosphorylation of ZDV in activated cells was shown to even overcome the increase in virus production induced by the activation, whereas ddI was not able to do so (53). These results suggest that the anti-HIV-1 activity of ZDV is superior in activated cells, whereas ddI is more effective in resting cells (52,53).…”

“…Like the activation of nucleosides, activation of ddN requires phosphorylation which is dependent on cellular kinases whose expression and activity are cell type specific (51)(52)(53). ZDV and stavudine (d4T) are phosphorylated by kinases that are only active in activated cells.…”

R5 Variants of Human Immunodeficiency Virus Type 1 Preferentially Infect CD62L−CD4+T Cells and Are Potentially Resistant to Nucleoside Reverse Transcriptase Inhibitors

“…Previous studies showed a lower potency of NRTI to block HIV replication in quiescent (G 0 ) CD4 ϩ T lymphocytes than in activated CD4 ϩ T cells (18,19,55). However, HIV-1 infection of quiescent (G 0 ) CD4 ϩ T cells is nonproductive, and it is cleared with a half-life of about 1 day (9,49,54,56,63,68).…”

“…As with quiescent (G 0 ) T cells (18,55), slowly dividing CD62L Ϫ CD4 ϩ T cells contain lower levels of thymidine kinase than do activated CD4 ϩ T cells. The NNRTI nevirapine was equally efficient in both cell systems.…”