To date, no approaches have been identified that reduce the replication-competent viral reservoir that persists during suppressive combination antiretroviral therapy (cART) by a degree large enough to consistently delay off-cART viral rebound. Early initiation of cART limits the size of the persistent viral reservoir that is established, making for a more tractable target for subsequent interventions. To evaluate the impact of substantial ablation of the viral reservoir in the setting of limited initial reservoir establishment, we administered a CD4-depleting antibody to SIV infected rhesus macaques that had initiated early cART.
Ten rhesus macaques started daily cART (TDF/FTC/DTG) 4 days post-infection (IV) with molecularly-barcoded SIVmac239M. Beginning at 30 weeks post-cART initiation, 5 animals received 5-6 biweekly doses of rhesusized CD4-depleting antibody; 5 animals served as controls. CD4+ cell depletion and cell-associated viral DNA (vDNA) levels were monitored in blood and lymph nodes (LN). Following the last dose of anti-CD4 antibody, animals remained on cART for 1 year. cART was then discontinued, with monitoring for viral rebound, rebounding viral variants in plasma, and estimation of viral reactivation rates.
By ~7 weeks post-cART initiation, plasma viral loads in all animals were stably suppressed to <15 viral RNA copies/ml. Consistent with limited reservoir establishment, cell-associated vDNA measurements were low in PBMC (median 1.7 vDNA copies/106 cells) and LN (median 2.1 vDNA copies/106 cells) pre-anti-CD4 administration, with no significant differences between experimental groups. Following anti-CD4 administration, CD4 T cell counts in blood declined by 96.3-99.9% and in LN by 78-91%. By one year after the last anti-CD4 treatment, CD4 counts returned in depleted animals to levels 23-65% lower than pre-depletion. Upon cART cessation, there was no significant difference between depleted and control groups, respectively, in time to first positive plasma viral load (median 27 days vs 17 days), unique rebounding variants (median 2 vs 4), or calculated reactivation rates (mean once per 6 days vs once per 3 days).…
Despite limited reservoir establishment with early cART, profound depletion of CD4+ T cells, including those potentially harboring virus, had no measurable impact on off-cART viral rebound. These findings underscore the potency that will be required of reservoir reducing strategies to meaningfully reduce total body reservoir size.