What’s All This Fuss I Hear About Viral “Blips”?

(See the Brief Report by Crowell et al on pages 2706–9.) During the inaugural season of Saturday Night Live in 1975, Gilda Radner’s Emily Litella character was a frequent guest on Weekend Update With Chevy Chase. Ms Litella typically would rant about a topic, starting her diatribe with the phrase, “What’s all this fuss I hear about …” and filling in the blank with topics ranging from “Russian jewelry” to “violins on television.” She would rant for a minute or so until Chase would interrupt her and indicate that her premise was wrong and that the real subject was Russian Jewry or violence on television, to which Ms Litella would respond meekly, “Never mind.” In the world of human immunodeficiency virus (HIV), ever since the initial use of HIV RNA (viral load) as a standard metric of antiretroviral (ARV) activity, viral “blips” have been observed in both clinical trials and routine practice. Blips are defined as transient elevations of viral load following a period of undetectable HIV RNA, usually at a single time point. After their initial description, investigators have debated the clinical meaning of blips, leading many clinicians to ask “What’s all this fuss I hear about viral blips?” Ultimately, clinical studies determined that isolated blips have very little clinical meaning [1–3], though the mechanism of how and why blips occur remained somewhat speculative [4]. In this issue of Clinical Infectious Diseases, Crowell and colleagues [5] present an analysis of the occurrence of viral blips over time among a cohort of patients who were identified during acute HIV infection. Fifty-five of 468 patients (16.9%) experienced ≥1 viral blip, with an incidence of 8.2 blips per person-years of follow-up. Notably, those who experienced blips had higher peak viral load values during seroconversion (6.6 vs 5.8 log10 copies/mL) than those who did not. Moreover, those who received ARV intervention at an earlier Fiebig stage (eg, stage I or II) had much fewer blipping episodes than those who received ARV therapy at later Fiebig stages (eg, stage IV or V). These data imply that persons with a larger initial viral reservoir during acute infection were more likely to “blip.” To put all of this into perspective, it is important to return to some basic principles of HIV biology. The amount of HIV in plasma (ie, the viral load) is known to be proportional to the number of cells in the body producing virus [6]. This means that higher plasma HIV RNA levels are associated with more cells in the host producing virus at any moment in time. Before ARV treatment, steady-state viremia, often referred to as the “viral load set point,” is maintained by the ongoing de novo infection of previously uninfected, activated CD4+ lymphocytes. The more cells infected and producing virus, the higher the viral load set point. Remarkably, with the average lifespan of an infected cell being only 1 day [7, 8], this means that, at steady state, once an infected cell dies it is replaced by precisely 1 newly infected cell. When ARV therapy is implemented, virtually all de novo infection ceases, and the viral load drops dramatically because the number of actively producing cells quickly die off and are not replaced by newly infected cells. This leads to a precipitous drop in the number of infected cells and hence a concomitant sharp reduction in viral load. Although most of the infected cells rapidly die, a small proportion (<1%) live on as chronic, latently infected CD4+ lymphocytes. These cells make up the “reservoir” of residual cells that can “ignite” periodically after cellular activation, releasing virus into the circulation, which results in transiently detectable virus. Indeed, a prospective study of blips demonstrated this phenomenon by showing that blips represent random variation around a suppressed HIV RNA level [9]. In the context of the findings reported by Crowell et al [5], a larger viral reservoir results in a higher likelihood of transient viremia, or blips. They showed increased frequency of blipping among those with higher peak HIV RNA levels during acute infection and initiation of ARV therapy at later Fiebig stages. These findings are supported by earlier studies showing that blips were associated with higher pretreatment viral set points, which are associated with more cells producing virus from a larger reservoir of chronically infected cells after treatment [1]. Taken together, the report by Crowell and colleagues [5] adds to the literature by demonstrating, once again, that blips result from random activation of latently HIV-infected cells in the viral reservoir, underscoring the proportional relationship between viral blips and the relative size of the reservoir. In other words, the size of the reservoir matters, as shown this time using peak viremia and Fiebig staging as surrogates for reservoir size. For clinicians in practice, most of whom have already embraced the notion that an isolated blip has no clinical meaning in terms of future potential virologic failure, these data help shed further light on the why and how of “blipping.” As for Emily Litella’s “What’s all this fuss I’m hearing about viral blips?” she can once again say, “Never mind,” but this time with more of an understanding of how blips happen. Potential conflicts of interest. The author: No reported conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.