Despite effective antiretroviral therapy, leading to ‘clinically undetectable’ levels of plasma HIV RNA (below 50 copies/ml), it has been demonstrated that very low levels of plasma HIV RNA remain detectable (4-8 copies/ml) in most induviduals. Understanding the source of this residual viremia will help finding a cure against HIV reservoirs.
HIV replication is a highly dynamic situation with a half-life of plasma viral RNA of about 2-3 hours. When antiretroviral therapy (ART) is initiated, HIV plasma RNA levels decrease dramatically, reaching less than 50 copies/ml within a few weeks. This level of 50 copies/ml is, actually, the cutoff of current clinical tests of viremia quantitation. This decrease, however, occurs with several steps or phases.
First, there is an exponential decrease of plasma viremia levels just after ART initiation, with a very short half-life of a few days, corresponding to HIV replication block in actively infected circulating CD4+ T cells.
Then, a second phase occurs, with a half-life of about 2 weeks, corresponding to HIV replication blockade in tissue cells, like macrophages and other tissue reservoir cells. In a third phase, there is a small decrease of HIV dynamics leading to very few levels of plasma viremia that finally remain stable (fourth phase of decay without slope). According to estimations done with this model of almost total HIV replication arrest, 60 to 70 years of effective ART would be necessary to finally eradicate the virus…
But even waiting is not that simple, as tiny levels of HIV RNA (les than 8 copies/ml) remain detectable in plasma in most patients using research assays.
The past 8 years have been animated by a large debate about the nature of this residual viral RNA in plasma: was it a proof of ongoing, very low, HIV replication, or was it only a release of HIV genetic material from already infected cells? This debate is not currently closed as both explanations could be valid. Against the ongoing replication theory is the fact that no drug resistance selection occurs at these very low levels of viremia. But the origin of these tiny amount of circulating plasma HIV RNAs even not clear at a cell level. It has been demonstrated that in half cases, it is genetically composed of a ‘predominant clone’ which is different from those present in circulating CD4+ cells.