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

Abstract

BackgroundAlthough combination antiretroviral therapy (cART) 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 cART to assess the effect of early treatment on cellular viral reservoirs.Methodology/Principal FindingsAcutely 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 cART. In a matched control-group of patients on successful cART 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 cART. After cART 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 cART in 42% of patients with cART initiated during acute infection as opposed to 87% of patients on cART 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.ConclusionEarly 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 cART. 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.

Replication of Human Herpesviruses Is Associated with Higher HIV DNA Levels during Antiretroviral Therapy Started at Early Phases of HIV Infection

“…Unspliced HIV RNA (usRNA) (Gag) and multiply spliced HIV RNA (msRNA) (Tat/Rev) PCRs were performed as a duplex with HEX (usGag) and FAM (msTat/Rev) probes, respectively, using primers and probes as previously described (20). Additionally, levels of all fully elongated and correctly processed HIV mRNA molecules (referred to as polyA) were measured as described previously (21).…”

Cytomegalovirus Replication in Semen Is Associated with Higher Levels of Proviral HIV DNA and CD4 + T Cell Activation during Antiretroviral Treatment

“…The cDNA product (8 l; approximately 200 ng) was added to the ddPCR reaction mixture. Unspliced HIV RNA (usGag) and multiply spliced (msTat-Rev) PCRs were performed as a duplex with HEX (usGag)-and FAM (msTatRev)-labeled probes, respectively, using primers and probes as previously described (30,31). The cycling conditions for this PCR were as follows: 10 min at 95°C, 60 cycles consisting of a 30-s denaturation at 94°C followed by a 60°C extension for 60 s, and a final 10 min at 98°C.…”

“…Analyses were performed on the complete data set of 53 subjects (including three subjects experiencing an HIV RNA blip of Ͻ200 copies/ml in the 3 months before sample collection) and on the reduced data set of 50 subjects with fully suppressed HIV RNA in blood plasma (Ͻ50 copies/ml). To estimate the average viral transcriptional activity per single HIV DNA copy (Pol), we calculated the ratio between cellular HIV RNA and total HIV DNA for each sample, as described previously (31,33). Because of the exploratory character of the study, we decided not to correct our results for false detection (multiple comparisons).…”

CD8+ T Cells Are Activated in an Antigen-Independent Manner in HIV-Infected Individuals

“…In this protocol, patients are offered early ART. After 1 y of suppressed viremia (,40 HIV-1 RNA copies/ ml plasma), patients can chose to interrupt ART (14)(15)(16)(17)(18). Study details are listed under http://www.clinicaltrials.gov; ID NCT00537966.…”