[Correlation between HIV-inhibiting drug activity in human macrophages and clinical outcome]

To assess the comparative efficacy of drugs inhibitors of human immunodeficiency virus (HIV) in human macrophages and lymphocytes, and to correlate the results with the clinical outcome.

Human primary macrophages and lymphocytes were infected with HIV in the presence of the following HIV inhibitors, all currently in clinical use: zidovudine, stavudine, zalcitabine, didanosine, lamivudine, PMEA, PMPA (all inhibitors of HIV reverse transcriptase), saquinavir and U-75875 (inhibitors of HIV protease).

All reverse transcriptase inhibitors tested showed a markedly higher antiviral activity in macrophages than in lymphocytes. Also protease inhibitors have a substantial anti-HIV activity in macrophages, yet their efficacy is markedly diminished if the drugs are added to macrophage culture after HIV, that is when the virus has established a chronical infection. Under these experimental conditions, however, only protease inhibitors among all HIV-inhibitors in clinical use are able to decrease virus replication in chronically-infected macrophages.

The results have strong clinical implications, due to the important role of macrophages in the pathogenesis of HIV infection. Macrophages are the major source of HIV at extralymphoid tissue levels, particularly in the central nervous system, where the blood-brain barrier strongly limits the penetration of antiviral drugs. For these reasons, only drugs, like stavudine and zidovudine, provided with good anti-HIV activity in macrophages, and reasonable barrier penetration have substantial chances to be effective in the central nervous system, and thus affect virus replication in a sanctuary where HIV hides and replicates out of the control of the immune system.