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. 1. Introduction 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 [1–3], 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]. Consequently, the interplay between HIV-1 infection in macrophages and macrophage-like cells is markedly less defined. Additionally, the relationship between in vitro observations and in vivo dynamics is not fully elucidated. Much evidence exists to support the existence of HIV-1 replication in macrophage/macrophage-like cells in vivo [5–11], including a recent report from Deleage et al., and confirmed the presence of HIV-1 in macrophages within seminal vesicles of patients on effective highly active antiretroviral therapy (HAART) [12]. Correspondingly, a variety of studies have presented evidence that monocytes harbor productive viral replication in patients receiving HAART [13, 14], with
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