Adverse Effects of Antiretroviral Drugs on HIV-1-Infected and -Uninfected Human Monocyte-Derived Macrophages

Abstract

Antiretroviral drugs approved for treatment of HIV-1 infection include nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs). Use of these drugs in combinations (highly active antiretroviral therapy) has delayed disease progression. However, long-term therapy is associated with potentially serious adverse effects. NRTIs are thought to contribute to these adverse effects via depletion of mtDNA. Inasmuch as macrophages (major targets for HIV-1) are highly metabolically active with large numbers of mitochondria, we investigated the effects of NRTIs (didanosine, stavudine, lamivudine, and zidovudine) on the viability and function of HIV-1-infected and -uninfected human monocyte-derived macrophages (MDMs). We demonstrate that the combinations didanosine/stavudine and lamivudine/zidovudine decrease mtDNA content in MDMs, with HIV-1-infected MDMs displaying a greater reduction than uninfected cells. This decrease correlated with decreased complement-mediated phagocytosis (C'MP) by MDMs, a process dependent on mitochondrial function. Inasmuch as PIs have previously been reported to interact with cellular proteases and given that cellular proteases are involved in the phagocytic process, we investigated the effects of the PI indinavir on C'MP. We demonstrate that indinavir augments C'MP by uninfected MDMs, but not HIV-1-infected MDMs. This study provides additional understanding on the effects of commonly used antiretroviral drugs on cellular immune function.

Long-acting slow effective release antiretroviral therapy

“…Thus achieving virologic cure through antiretroviral drugs (ARVs) currently remains a formidable and perhaps an improbable obstacle to overcome [4, 5, 6]. This is further complicated by limited access to ART seen commonly in resource-limited countries, adverse drug side effects, viral mutation rates that have led to emergence of resistant viral strains and poor patient compliance to lifelong therapy due to psychological, physical and drug addictions [7, 8, 9, 10]. Thus, the need for the development of reservoir targeted long acting slow effective release (LASER) ART delivery platforms cannot be overstated.…”

Nano-NRTIs: Efficient Inhibitors of HIV Type-1 in Macrophages with a Reduced Mitochondrial Toxicity

“…According to Azzam et al [36], treatment by AZT (up to 25 μg/mL, or 0.1 mM) did not affect the mtDNA content in MDMs, but could result in potent mitochondrial toxicity in other tissues/cells (e.g., muscles, heart, liver), while ddI had one of the highest potency of the inhibition of polymerase gamma in mitochondria among NRTIs. Although we observed no effect of AZT and a moderate effect of AZT+ddI mixture on the mtDNA content in MDMs, an substantial increase in mtDNA content was detected after the prolonged treatment by many of Nano-NRTIs (Fig.…”

The Mechanism Underlying Defective Fcγ Receptor-Mediated Phagocytosis by HIV-1-Infected Human Monocyte-Derived Macrophages

“…Where 3TC was added during infection, the drug was maintained in the medium throughout subsequent culturing. The 3TC concentration used was not toxic to the cells for the duration of the experiments, as previously reported (39). In selected experiments, adherent MDM cultured in 24-well plates were infected with HIV-1 NL(Ba-L) ⌬nef-EGFP at indicated multiplicity of infection.…”