From ‘purging’ to ‘endogenization’ of the HIV genome: a new approach to HIV eradication?

Abstract

The development of antiretroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV) infection represents one of the greatest achievements of modern medicine. ART has significantly changed the clinical outcome of HIV-infected individuals, the rates of HIV-related mortality/ morbidity and the nature/transmission of HIV-1 infection in countries with access to antiretroviral drugs [1]. It is now evident, however, that this approach cannot rapidly lead to a cure for HIV infection. Indeed, the virus may still persist in specific reservoirs even in treated patients in whom viraemia is well controlled [2,3]. More intriguingly, the fact that treated patients may present a residual immune dysregulation associated with chronic immune activation [4] makes HIV eradication an aspirational goal. In addition to causing uncertainty, this has led us to consider the topic of HIV eradication with some scepticism. All these considerations, alongside issues of compliance, drug access and toxicity linked to chronic therapy, highlight the need to implement different and innovative strategies in the field of HIV eradication. In other words, together with an extensive approach to the issue from a traditional schemedriven point of view, we need to continue to investigate HIV eradication from a completely new and ground-breaking standpoint. One possibility is to extrapolate and apply to the HIV field findings and knowledge from areas only potentially related to the HIV issue. In this context, the paper by Didier Raoult’s group published in this issue of CMI [5] represents an interesting and challenging approach to the topic. It is a radical change resulting from the use of advanced molecular techniques. The authors speculate that the persistence of HIV-DNA in the host genome should no longer be considered an obstacle to HIV eradication but, rather, the beginning of a process of HIV endogenization that may ultimately lead to eradication of HIV infection from the human species. Starting from the fact that the characterization of ‘HIV elite controller’ status (i.e. subjects achieving long-term control of viraemia without highly active antiretroviral therapy [6,7]) has not yet been elucidated, the study monitored two HIV-infected patients (one subject for more than 10 years) with no HIV-related disease and no detection of plasma HIV RNA or cell-associated HIV DNA with routine tests. Both subjects were infected at different times and in different ways and are immunologically reactive against HIV proteins (indicating that they were actually infected). However, their PBMCs harbour very few copies of integrated HIV-DNA (detected only when new molecular techniques are used) that are not replication-competent, probably due to the high content of transcription stop signals. The authors assumed that APOBEC3G, a well-known cytosine deaminase that can be encapsidated and may subsequently hypermutate the neosynthetized cDNA inside the virion during reverse transcription, might be functionally involved in inducing such high defectivity in the HIV genome. The literature on the acquisition of retroviruses in the