Antiretroviral Therapy in Macrophages: Implication for HIV Eradication

Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
Antiviral chemistry & chemotherapy 10/2009; 20(2):63-78. DOI: 10.3851/IMP1374
Source: PubMed


HIV type-1 (HIV-1) accounts for more than 25 million deaths and nearly 40 million people are infected worldwide. A significant obstacle in clearing virus from infected individuals is latently infected viral reservoirs. Latent HIV-1 can emerge with recrudescence as a productive infection later in disease progression and could provide a source for the emergence of resistant HIV-1. It is widely recognized that macrophages represent a latently infected viral reservoir and are a significant and critical HIV-1 target cell in vivo. Macrophages can be divided into multiple subsets of macrophage-like cells, all of which are susceptible to HIV-1 infection, including dendritic cells, Langerhans cells, alveolar macrophages, mucosal macrophages and microglial cells. Current antiretroviral therapy (ART) often displays differential antiviral activity in macrophages relative to CD4(+) T-lymphocytes. Significant work has been performed to establish antiviral activity of many clinically approved ART in macrophages; however, a direct link between antiviral activity and specific mechanisms responsible for these antiviral effects are incompletely understood. This review identifies many understudied areas of research, along with topics for further research in the field of HIV therapy and eradication. Discussion focuses upon the known cellular pharmacology and antiviral activity of antiretroviral agents in macrophages and its relationship to latency, chronic HIV-1 infection and therapeutic strategies to eradicate systemic HIV-1 infection.

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Available from: Raymond F Schinazi
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    • "In lymphocytes but not monocytes, the negative side-effects of ART (mitotoxicity) on mitochondria could be balanced by the positive effects of ART, i.e. decreased viral load and replication [94]. ART antiviral activity is less effective towards chronically infected monocytes than lymphocytes for several reasons, one of them being that HIV-related ART targets are present in lower amounts in refractory monocytes [95]. Moreover, the different mitochondrial sensitivities to ART could also be the result of distinct pathways involved in ART intracellular metabolism (e.g. "
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    • "Macrophages are a key reservoir for HIV-1, and their ubiquitous nature, multiple, and often independent microenvironments in which they are contained, coupled with their susceptibility to HIV-1 infection [1] [2] [3], dictate that further understanding must be garnered about the distinctive characteristics of macrophages and the subsequent impact on the dynamics of HIV-1 infection in these cells. Despite these factors, most of the attention on reservoirs for latent HIV- 1 has focused on cells of lymphoid origin, most notably CD4 + /CD45RO + memory lymphocytes [4]. "
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    ABSTRACT: Macrophages are ubiquitous and represent a significant viral reservoir for HIV-1. Macrophages are nondividing, terminally differentiated cells, which have a unique cellular microenvironment relative to actively dividing T lymphocytes, all of which can impact HIV-1 infection/replication, design of inhibitors targeting viral replication in these cells, emergence of mutations within the HIV-1 genome, and disease progression. Scarce dNTPs drive rNTP incorporation into the proviral DNA in macrophages but not lymphocytes. Furthermore, the efficacy of a ribose-based inhibitor that potently inhibits HIV-1 replication in macrophages, has prompted a reconsideration of the previously accepted dogma that 2'-deoxy-based inhibitors demonstrate effective inhibition of HIV-1 replication. Additionally, higher levels of dUTP and rNTP incorporation in macrophages, and lack of repair mechanisms relative to lymphocytes, provide a further mechanistic understanding required to develop targeted inhibition of viral replication in macrophages. Together, the concentrations of dNTPs and rNTPs within macrophages comprise a distinctive cellular environment that directly impacts HIV-1 replication in macrophages and provides unique insight into novel therapeutic mechanisms that could be exploited to eliminate virus from these cells.
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