It is possible, for example, that residual replication could be further suppressed simply by strengthening standard therapy regimens. development. Keywords:latency, HAART, antiretroviral, therapy, AIDS == Introduction == Human immunodeficiency virus (HIV) establishes a persistent, lifelong contamination, which if left untreated almost invariably leads to acquired immunodeficiency syndrome (AIDS) and death of the infected individual. Over the past 25 years, significant advances have been made in the development of antiretroviral brokers that can potently suppress viral replication and prevent progression to AIDS. However, the drugs used in combination during highly active antiretroviral therapy (HAART) are associated with significant problems, including toxic side effects, high pill burden, development of virological resistance and great financial expense. More importantly, HAART does not completely eliminate HIV from the body, meaning that if treatment is usually stopped, residual virus present in several potential reservoirs rapidly expands allowing disease progression to continue.1,2Understanding the sources of replication-competent Pou5f1 HIV that persist during therapy and developing methods to purge these viral reservoirs have therefore become important areas of research focus. == Mechanisms of HIV persistence during HAART == Perhaps, the most well-defined viral depository during therapy is the latent reservoir within memory CD4+ T cells.3,4It is believed that HIV latency is generally established when an activated CD4+ T cell becomes infected by HIV but transitions to a memory cell before it can be killed by the virus. This transition is usually associated with a number of cellular changes, including a reduction in the levels of several transcription and other factors that are required by HIV for its replication. Because memory cells are by nature very long-lived, the host cell can then persist for decades with its silent viral cargo before receiving a stimulatory signal that activates the cell and concomitantly induces virus production from Nedocromil sodium the latent HIV genome. Latently infected cells are rare, representing around one per million CD4+ T cells, which translates to a total of 1 1 million latently infected cells in the body as a whole. 5These cells also decay very slowly during HAART, with an average half-life of 44 months. It is therefore estimated that under current antiretroviral regimens, complete depletion of this reservoir would take over 60 years,4even if there were no further viral replication or replenishment of the reservoir during therapy. The situation is usually further complicated because in addition to the latent reservoir, other cryptic viral sources exist during HAART, including a Nedocromil sodium very small Nedocromil sodium amount of active virus replication that occurs even during therapy.6It is not clear whether this is due to poor antiretroviral drug penetration into the sites of virus replication or because of residual replication that occurs even under optimal drug concentrations. Even more enigmatic sources of virus have also been identified in some patients, although their precise cellular origin is usually unclear.7,8 The issue of latency and these other obstacles have led some researchers to voice uncertainty over whether HIV infection can ever be cured. However, a number of strategies are currently being investigated that, if successful, may ultimately aid in the durable, lifelong suppression of HIV, or perhaps even the elimination of the virus altogether. == Improving long-term virus suppression == In order to cure an HIV-infected individual, all sources of replication-competent HIV must be eliminated. Achieving this goal may require a combination of different approaches, reflecting the variety of reservoirs that exist in infected patients. With this in mind, perhaps the most tractable hurdle is the persistent replication that occurs during HAART. It is possible, for example, that residual replication could be further suppressed simply by strengthening standard therapy regimens. This may be achieved by enhancing currently available antiretrovirals, either by improving bioavailability and pharmacokinetic properties of current drugs or by developing new ones that target different viral proteins and stages of the virus life cycle. Recent examples of newly approved antiretrovirals are the entry inhibitor maraviroc (UK-427857)9and the integrase inhibitor raltegravir (MK-0518).10The field is eagerly awaiting the results of studies investigating whether addition of these or other novel agents11, 12to current HAART regimens will further suppress viraemia, which would indicate that residual replication can indeed be inhibited by intensification of HAART. One interesting observation in this area is usually that raltegravir treatment appears to suppress plasma viral loads in infected patients more rapidly Nedocromil sodium than treatment with other antiretrovirals.13While the direct cause of this phenomenon is not clear, it does demonstrate that antiretrovirals with.