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Purpose: 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., Materials and Methods: 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)., Results: 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., Conclusions: 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.

In this paper we describe the current status of the chemotherapy of HIV-related disease, and the newly emerging approaches to this problem. Azidothymidine, the first anti-HIV drug, is now used by thousands of patients with AIDS, and is able to induce a substantial improvement of their clinical status. However, due to its toxicity and its very limited activity against HIV replication in chronically infected cells (the natural reservoir of the virus in the body), it is crucial that new drugs be developed. A number of compounds belonging to the dideoxynucleoside family (the same of AZT) have been synthesized and used in HIV-infected patients, with promising results. Nevertheless, new compounds with different mechanisms of action, and with excellent anti-HIV efficacy need to be developed, particularly those that can inhibit the late stages of HIV replication. This will permit a polychemotherapeutic approach against HIV infection that, as in the case of anticancer chemotherapy, has conceivably better chances to be effective in patients with HIV-related disease.

The pathogenesis of HIV infection and the definition of the cell types target of HIV is the crucial background for the improvement of the therapeutic strategies against HIV infection. Monocyte-macrophages (M/M) are easily infected by HIV, and play a crucial role in the maintenance and the progression of HIV-related disease; HIV infection of M/M is the principal cause of HIV-related "dementia complex". Thus it is crucial that drugs used in the therapy of HIV infection are active against HIV replicating in cells of M/M lineage. In this paper the interaction between HIV and M/M is analyzed and the characteristics of viral replication in these cells, and the in vitro antiviral activity of several drugs in M/M are discussed. These data suggest that patients should be treated with drugs, that inhibit HIV also in M/M and, consequently, are able to block the clinical manifestations related to M/M infection, such as "dementia complex".

Levels of replication of HIV in two different populations of monocyte/macrophages (M/M) at different stages of maturation were evaluated, as well as the antiviral activity of alpha-interferon (alpha-IFN) and Ampligen (an inductor of endogenous production of alpha-IFN). HIV replication was found to be 5-10 times greater in mature than in young M/M. Furthermore, alpha-IFN and Ampligen showed a substantial anti-HIV activity in young M/M, while little effect was achieved in mature M/M. Finally, HIV replication in chronically-infected M/M was not affected by alpha-IFN. These results suggest that alpha-IFN might be useful in combination with other anti-HIV drugs in the therapy of HIV-related disease.