New drug combinations for the treatment of murine AIDS and macrophage protection

Abstract

The failure of highly active antiretroviral therapies (HAART) is mainly due to the existence of latent infected reservoirs, such as macrophages and resting CD4+ T cells. In this paper, we report the results that we obtained in a murine model of AIDS by alternating the administration of the lympholitic drug 2-Fluoro-ara-AMP (Fludarabine) to eliminate the infected cells, with that of Azidothymidine (AZT) plus reduced glutathione (GSH) encapsulated in erythrocytes, to protect lymphocytes and macrophages not yet infected, respectively. Two groups of infected mice were treated as follows: one group was treated by alternating the administration of Fludarabine and AZT (treatment A), while the other group received the same treatment plus GSH-loaded erythrocytes given with AZT (treatment A + L-RBC). Fludarabine was administered intraperitoneally, AZT in the drinking water and GSH was encapsulated in erythrocytes by a procedure of hypotonic dialysis and isotonic resealing. The results obtained show that GSH-loaded erythrocytes provide additive effects in all the parameters examined. Alternation of a lympholitic drug and antiretroviral drug is effective in reducing the progression of murine AIDS. Addition of a system to protect macrophages provides additive effects in almost all the parameters considered, confirming that combination therapies aimed at protecting different infectable cell compartments are better than treatments protecting mainly lymphocytes.

Targeting Cysteine Residues of Biomolecules: New Approaches for the Design of Antiviral and Anticancer Drugs

“…The mechanism of action of such derivatives may be similar to the one of the zinc-ejecting derivatives, except that the Another recent report deals with the use of a new combination therapy against murine AIDS, which contains the well-known antiretroviral agent AZT (a reverse transcriptase inhibitor), the lympholytic drug fludarabine (2-fluoro-ara-AMP) and reduced glutathione encapsulated erythrocytes, in order to protect lymphocytes and macrophages not yet infected by the virus [35] (see also the [30]. The target protein may be PDI for 11a or metallothionein for 11b .…”

“…detailed discussion on glutathione in section 3.3 of this review). This treatment was very effective in reducing disease progression in infected mice, and probably represents the first successful approach for eliminating HIV from cells where virus replication continues even under HAART [35].…”

Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics

“…MAIDS is characterized by physiological abnormalities which are similar to those observed in the early stages of human AIDS. Hence, this model may be used to provide insights into the immunosuppressive changes characterizing human retrovirus infections, which in turn could lead to new antiretroviral drugs and new pharmacological approaches (5)(6)(7)(8)(9)(10).…”

Infectious Diseases: Need for Targeted Drug Delivery

“…Viral replication is inhibited by the antioxidant glutathione. Erythrocytes containing glutathione (GSH) in combination with azidothymidine (AZT) and didanosine (DDI) showed higher reduction in viral DNA in bone marrow and brain as compared to DDI + GSH alone [ 247 ]. Immunoliposomes containing siRNA for targeting the lymphocyte function-associated antigen-1 (LFA-1) integrin, which is expressed on all leukocytes, was selectively taken up by T cells and macrophages, the primary site of HIV.…”