Impact of alemtuzumab-mediated lymphocyte depletion on SIV reservoir establishment and persistence.

Persistence of the rebound-competent viral reservoir (RCVR) within the CD4⁺ T cell compartment of people living with HIV remains a major barrier to HIV cure. Here, we determined the effects of the pan-lymphocyte-depleting monoclonal antibody (mAb) alemtuzumab on the RCVR in SIVmac239-infected rhesus macaques (RM) receiving antiretroviral therapy (ART). Alemtuzumab administered during chronic ART or at the time of ART initiation induced >95% depletion of circulating CD4⁺ T cells in peripheral blood and substantial CD4⁺ T cell depletion in lymph nodes. However, treatment was followed by proliferation and reconstitution of CD4⁺ T cells in blood, and despite ongoing ART, levels of cell-associated SIV DNA in blood and lymphoid tissues were not substantially different between alemtuzumab-treated and control RM after immune cell reconstitution, irrespective of the time of alemtuzumab treatment. Upon ART cessation, 19 of 22 alemtuzumab-treated RM and 13 of 13 controls rebounded in <28 days with no difference in the time to rebound between treatment groups. Time to rebound and reactivation rate was associated with plasma viral loads (pVLs) at time of ART initiation, suggesting lymphocyte depletion had no durable impact on the RCVR. However, 3 alemtuzumab-treated RM that had lowest levels of pre-ART viremia, failed to rebound after ART withdrawal, in contrast to controls with similar levels of SIV replication. These observations suggest that alemtuzumab therapy has little to no ability to reduce well-established RCVRs but may facilitate RCVR destabilization when pre-ART virus levels are particularly low. Author summary: A major challenge to curing HIV is the presence of cells with rebound-competent viral reservoirs (RCVR) capable of re-establishing systemic infection when ART is interrupted. CD4⁺ T cells harboring RCVR persist for life due to homeostatic mechanisms that allow them to proliferate and expand during ART. In this study, we explored whether pan-lymphocyte depletion with a licensed CD52-depleting monoclonal antibody called alemtuzumab, can eliminate or reduce RCVR in SIV-infected rhesus macaques (RM) when administered either at the time of ART initiation or during chronic ART administration. While alemtuzumab induced massive depletion of lymphocytes in blood, including >95% depletion of CD4⁺ T cells, there were no measurable effects of alemtuzumab on cell-associated viral loads during ART or SIV rebound dynamics following ART interruption in most RM. Three alemtuzumab-treated RM failed to manifest rebound viremia during extended follow up after ART withdrawal. However, these animals had the lowest levels of pre-ART SIV replication, suggesting that alemtuzumab may have been effective in RM with early and presumably smaller RCVR. Overall, our study highlights the current limitations of lymphocyte depletion strategies in facilitating the permanent disruption of RCVR, particularly once the RCVR is established above levels that induce consistent post-ART viremia. [ABSTRACT FROM AUTHOR]