Profound Depletion of HIV-1 Transcription in Patients Initiating Antiretroviral Therapy during Acute Infection.
Schmid A, Gianelle S, von Wyl V et al. PLoS ONE 5 (10): e13310
The main aims and rationales for antiretroviral therapy in acute HIV-1 infection are confinement of genetic diversity of viral quasispecies to prevent escape from adaptive immunity, restriction of CD4+ T-cell loss, preservation of immune functions, and inhibition of initial viral spread throughout the possible sites of replication. Despite considerable efforts from various research groups, to date evidence from clinical studies in humans to empirically substantiate these concepts remains limited. The authors performed a longitudinal in-depth analysis using patient matched highly sensitive qPCR assays to detect different HIV-1 gene transcripts to assess effects of early ART intervention….
Acutely HIV-1 infected patients (n= 24) were treated with ART within 3–15 weeks after infection. To investigate the activity of the HIV-1 infected cells, distinct PBMC-associated viral RNA species (vRNAs) were quantified:
- unspliced RNA (UsRNA)
- and 2 types of multiply spliced encoding: tat and rev (MsRNA-tatrev) or nef (MsRNA-nef).
These RNAs were known to be expressed both in latently and productively infected cells, however, at much higher levels in the latter cell population. As a marker for productively infected cells, PBMC-associated extracellular virion RNA (vRex) was also measured.
Initiation of ART resulted in a decay of viral RNA production. Whereas plasma viremia followed kinetics which were consistent with a 2–3 phasic exponential decay, vRex dropped to undetectable levels almost instantly after initiation of ART. Decay of UsRNA and MsRNAs was intermediate between that of plasma viremia and vRex.
Upon initiation of ART, disappearance of vRex took a median time of 4.5 weeks.
Taking into account that the second sample following baseline in the current study was obtained at a median time of 4.4 weeks depletion of vRex occurred instantaneously after ART initiation. MsRNAs declined significantly later to undetectable levels, namely within a median time of 8.4 weeks. The next parameter to reach its detection limit with a significant delay compared to MsRNA was UsRNA with a median time to the first undetectable measurement of 13.5 weeks. Finally, plasma viremia dropped to undetectable levels within a median time of 24.6 weeks, which was not significantly different to the decay of UsRNA.
After cessation of ART, plasma viremia reached levels above the threshold of 50 copies/ml in a median time of 4.2 weeks. Rebound of UsRNA and MsRNA proceeded with some delay without reaching statistical difference: median time to rebound was 8.0 weeks and 9.8 weeks for UsRNA and MsRNA, respectively. Lastly, within a median time of 17.9 weeks, vRex rose to detectable levels. Its rebound was statistically different from that of plasma viremia and of UsRNA but not from MsRNA.
To investigate whether ART initiated in acute infection had an impact beyond its cessation, the levels of HIV-1 nucleic acids at baseline and after treatment cessation were compared. The authors found a less pronounced impact of early ART on cellular viral nucleic acid levels after treatment cessation. Only MsRNA-nef showed persistent significant reduction after ART, whereas the remaining parameters, vDNA, vRex, UsRNA, and MsRNA-tatrev tended to be lower after treatment stop compared to baseline but without reaching statistical significance.
HIV-1 DNA persisted at a level of 8236253 copies/106 PBMC during ART initiated in acute infection. However, proviruses in these infected cells were transcriptionally almost completely silent. Only expression of UsRNA was occasionally detected at a mean level of 2.661.2 copies/106PBMC.
The major finding of this study was that early ART initiated during acute HIV-1 infection significantly depleted the number of transciptionally active proviruses by an order of magnitude when compared to levels detected in patients treated during chronic infection.
Decay of HIV-1+ cells in response to treatment occurred in a significantly staggered mode according to their pattern of viralRNA expression and life-span. Productively infected cells expressing vRex vanished almost instantly after initiation of treatment, then cells expressing MsRNA followed with a delay of about 4 weeks, ultimately a further 5 weeks later, cells expressing solely UsRNA pursued. Thus, even HIV-1 RNA expressing cells with the longest life spans approached depletion. These findings imply that early ART led to the clearance of long-lived cells harboring transcriptionally active latent proviruses.
After cessation of ART, virological parameters reappeared inverted to their decay.
The observations that viral rebound in plasma preceded that of cellular viral RNAs and plasma viremia was the last parameter to decay during ART, implies that PBMC can be viewed as independent compartment to some degree separate from the source of virus appearing in plasma.
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Key words: ART, HAART, acute HIV infection, benefit, eradication, primary HIV infection, provirus, replication, reservoir