therapy initiated in the acute phase of HIV-

Treatment

Profound Depletion of HIV-1 Transcription in Patients Initiating Antiretroviral Therapy during Acute Infection

Although combination antiretroviral therapy initiated in the acute phase of HIV-1 infection may prevent expansion of the latent reservoir, its benefits remain controversial. In the current study, HIV-1 RNA transcription patterns in peripheral blood mononuclear cells (PBMC) were monitored during acute antiretroviral therapy to assess the effect of early treatment on cellular viral reservoirs. Acutely HIV-1 infected patients (n = 24) were treated within 3-15 weeks after infection. Patients elected to cease treatment after ≥1 year of therapy. HIV-1 DNA (vDNA), HIV-1 RNA species expressed both in latently and productively infected cells, unspliced (UsRNA), multiply spliced (MsRNA-tatrev; MsRNA-nef), and PBMC-associated extracellular virion RNA (vRex), expressed specifically by productively infected cells, were quantified in PBMC by patient matched real-time PCR prior, during and post antiretroviral therapy. In a matched control-group of patients on successful antiretroviral therapy started during chronic infection (n  = 15), UsRNA in PBMC and vDNA were measured cross-sectionally. In contrast to previous reports, PBMC-associated HIV-1 RNAs declined to predominantly undetectable levels on antiretroviral therapy. After antiretroviral therapy cessation, UsRNA, vRex, and MsRNA-tatrev rebounded to levels not significantly different to those at baseline (p>0.1). In contrast, MsRNA-nef remained significantly lower as compared to pretreatment (p = 0.015). UsRNA expressed at the highest levels of all viral RNAs, was detectable on antiretroviral therapy in 42% of patients with antiretroviral therapy initiated during acute infection as opposed to 87% of patients on antiretroviral therapy initiated during chronic infection (Fisher's exact test; p = 0.008). Accordingly, UsRNA levels were 105-fold lower in the acute as compared to the chronic group. Early intervention resulted in profound depletion of PBMC expressing HIV-1 RNA. This is contrary to chronically infected patients who predominantly showed continuous UsRNA expression on antiretroviral therapy. Thus, antiretroviral treatment initiated during the acute phase of infection prevented establishment or expansion of long-lived transcriptionally active viral cellular reservoirs in peripheral blood.

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Editors’ note: This study of antiretroviral treatment in 24 acutely-infected individuals contributes tantalizing findings to a small but growing body of literature. Antiretroviral treatment does not eradicate HIV from the body or induce safe treatment-free periods – once you start you are on it for life. This study suggests that it may be possible to reduce the latent reservoir of HIV during early treatment. Antiretroviral therapy in acute infection appeared to have led to the clearance of long-lived cells harbouring latent proviruses that can be transcriptionally active, meaning that they were in waiting for a chance to pounce. Larger studies have included the QUEST study, the CASCADE study, the SETPOINT trial, and other studies that have attempted to answer the question of whether starting antiretroviral treatment during acute HIV infection is worth the drug toxicity, resistance, pill burden, and quality of life. We need proof of concept studies to determine whether the ‘hit early and hard’ adage of Paul Ehrlich for the treatment of infectious diseases really would work to limit HIV’s population size, toxicity, and potential to escape immunological and chemotherapeutic/medical control.