The HIV-1 reservoir is the major hurdle to cure. Thus, understanding factors affecting size and decay of this reservoir is crucial for development of cure strategies.
In 1,078 patients (pt) enrolled in the Swiss HIV Cohort Study, who after initiating their 1st triple combination antiretroviral therapy (cART) were fully suppressed for >5 yr (< 50 HIV RNA cp/ml of plasma), we measured total HIV-1 DNA levels at 3-4 time points using droplet digital PCR (in total 3,546 samples). Focusing on the time after the 1st rapid decay of HIV-1 DNA we chose the 1. time point 1.49 yr (IQR=[1.27,1.7], N=1,078) after ART initiation, the 2. time point 2 yr later (IQR=[1.87,2.16], N=1,068) and the 3. time point on average 1.93 yr (IQR=[1.77,2.15], N=1,071) thereafter. Total HIV-1 DNA in a 4th sample was quantified for a subset of pt 4.92 yr (IQR=[3.28,6.02], N=429) later. This extensive data set enabled a systematic investigation of parameters that potentially steer decay dynamics of the HIV-1 reservoir in infected individuals on long-term successful ART.
Total HIV-1 DNA levels significantly decreased between our sampling times with diminishing differences over time (Fig 1). Further, our data identified pre-cART RNA levels, viral subtype, risk group injecting drug user, time to suppression, blips before 1st sample and infection stage at cART start to be independent drivers of the initial total HIV-1 DNA level. Studying decay slopes for each pt, pre-cART CD4 cell count, pre-cART CD4/CD8 ratio, pre-cART viral load and viral blips were significant drivers in the univariate model. The type of treatment (NNRTI vs boosted PI based cART) showed no differential effect on the decay. However, in multivariable analysis a very strong and independent inhibitory effect on total HIV-1 DNA decay was governed by viral blips. To conclude, our data confirm relevant drivers of the establishment and the depletion of the viral reservoir and reflect a highly interesting causal interplay between intermittent replication and dynamics of total HIV-1 DNA of patients on successful therapy.
The size of the viral reservoir as measured by total HIV-1 DNA in this large study is strongly governed by time of cART initiation. Strikingly, the main independent predictor of total HIV-1 DNA decay were viral blips, which had a strong inhibiting effect. Thus, viral blips are of biological relevance for the latent reservoir and this may have implications for cure research.