Between the mid to late 1990’s, the development and introduction of combination antiretroviral therapy (c-ART) transformed the landscape of HIV care for those with access to treatment. Extrapolating from initial responses to treatment, there was hope that some patients might be cured of infection after several years of c-ART ¹. In late 1997, our group and two others demonstrated that a reservoir of latently infected cells persisted in patients despite fully suppressive antiretroviral therapy^2-4. We showed that this persistence was not the consequence of treatment failure or the development of antiretroviral drug resistance. These latently infected cells harbored replication competent provirus that could give rise to propagating infection in vitro thus predicting that treatment interruption could result in viral reactivation and rebound.  

In the years since these initial reports, the capacity of this reservoir to rekindle infection in patients who stop treatment has been confirmed. The observed decay half life of these latently infected cells in patients on suppressive ART is estimated to be about 44 months, effectively ensuring lifelong persistence with contemporary therapy⁵. Besides translating to a requirement for lifelong treatment with c-ART, we have learned that viral persistence is accompanied by continued immune dysregulation that may underpin many non-AIDS medical conditions that erode health and limit the life expectancy of even those receiving effective c-ART^6,7.  For these reasons, it remains imperative to better understand the latent reservoir and how to control and eliminate it.

Hope that HIV eradication from infected patients could be achieved was renewed with reports that “the Berlin patient”, Timothy Brown was HIV-free following successive allogeneic bone marrow transplantation from a donor homozygous for the delta-32 CCR5 polymorphism that protects cells from infection^8,9.  Whether interventions not associated with the risks and costs of bone marrow transplantation can result in viral eradication has been the subject of much study.  The principal HIV reservoir in the setting of suppressive ART are memory CD4 Tcells (although other cellular reservoirs likely also exist) whose role in immunologic memory confer intrinsic attributes of stability and longevity that may be further augmented by renewal mechanisms through cellular proliferation¹⁰

The key attribute of HIV latency is the absence of sufficient viral expression to induce cytopathic effects or immune recognition to trigger the clearance of the infected cell¹⁰. Consequently, eradication strategies have been based on inducing virus expression sufficient to trigger clearance, so called “shock and kill”¹¹. Indeed, attempts at viral reactivation in vivo appears at least partially successful but these interventions have yet to yield measurable reductions in reservoir size^12-14.  Optimizing strategies to achieve latency reversal will require a better understanding of the blocks to HIV expression in vivo. Contrary to standard models that suppose a near absence of HIV transcription, Yukl observed that many abortive viral RNA transcripts are present in unstimulated Tcells from patients on c-ART (approximately 20/provirus) but that blocks to elongation, RNA completion and splicing are the key restrictions to HIV expression suggesting possible targets for more effectively overcoming viral latency¹⁵.  Finally, cure research now also explores enhancing the “kill” arm of the shock and kill strategy including boosting adaptive immune control through vaccination, use of monoclonal antibodies to elicit ADCC, enhancement of innate immune control and novel cellular therapies^16-20.

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