Treatment of Early HIV Infection Reduces Viral Reservoir to Levels Found in Elite Controllers
Maria Buzon*1,2, K Seiss2, A Stone2, F Pereyra2,3, E Rosenberg1, X Yu2, and M Lichterfeld1
1Massachusetts Gen Hosp, Boston, US; 2Ragon Inst of MGH, MIT, and Harvard, Boston, MA, US; and 3Brigham and Women`s Hosp, Boston, MA, US
Background: Integrated HIV-1 DNA represents a long-lived viral reservoir that persists in infected cells during ART. Treatment initiation during early stages of HIV-1 infection may reduce the size and decay kinetics of the latent reservoir, and allow for a functional cure of HIV-1 infection that mimics natural viral control observed in elite controllers (EC). Here, we investigated HIV-1 reservoirs in a unique cohort of patients who started treatment early during infection and remained on fully suppressive HAART for >10 years.
Methods: CD4+ cells were isolated after a median of 10 years of undetectable viremia from 37 treatment-naïve EC, 10 patients who initiated ART in the chronic phase of infection (chronic treated), and 8 patients initiating ART within 90 days of infection (early treated). Levels of total, integrated and 2-LTR HIV-1 DNA were measured by qPCR. In addition, integrated HIV-1 DNA in acute treated patients was longitudinally measured in 3-year intervals, and decay kinetics was calculated using linear regression with first order kinetics.
Results: Pre-treatment HIV-1 RNA levels and CD4 counts were not significantly different between acute treated vs chronic treated cohorts (p = 0.62 and p = 0.36, respectively). In comparison to chronic treated patients, levels of integrated and total HIV-1 DNA were significantly lower in EC (p = 0.003 and p <0.0001, respectively) and patients treated during acute infection (p = 0.06 and p = 0.001, respectively). 2-LTR circles were also more frequently detected in chronic treated (5/10) than EC (3/37) (p = 0.002) and early treated subjects (1/8)(p = 0.09). In addition, the ratio between total and integrated HIV-DNA was significantly lower in early compared to chronic treated patients (p = 0.04) and EC (p = 0.04). The calculated half-life of integrated HIV-1 DNA in early treated patients was 61 months, consistent with the extremely long persistence of latently infected cells.
Conclusions: Initiation of ART during the early disease process, followed by prolonged therapy for >10 years, reduces integrated and total HIV-1 DNA to levels observed in EC. Moreover, extrachromosomal HIV-1 DNA was lower in early treated subjects, suggesting reduced residual HIV-1 replication in these patients. These data contribute to increasing evidence that prolonged ARV initiated during primary infection may allow for a clinically significant depletion of HIV-1 reservoirs.