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 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.

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Publication Details

Journal
PLoS Pathogens
Published
2024-08-22
DOI
https://doi.org/10.1371/journal.ppat.1012496
Citations
2
Primary Topic
Phagocytosis and Immune Regulation
Type
article
Field-Weighted Citation Impact
0.48

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article

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

Jacob D. Estes, Miles P. Davenport, Christine M. Fennessey, Randy Fast et al.
2 citations
PLoS Pathogens
Phagocytosis and Immune Regulation
0.48
article

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

Jacob D. Estes, Miles P. Davenport, Christine M. Fennessey, Randy Fast, Caralyn S. Labriola, Rhonda MacAllister, Afam A. Okoye, William J. Bosche, Kathleen Busman‐Sahay, Alejandra Marenco, Paul T. Edlefsen, Michael K. Axthelm, Lorna Silipino, William Goodwin, Jeffrey D. Lifson, Derick M. Duell, Morgan Chaunzwa, Rebecca Shoemaker, Brandon F. Keele, Kelli Oswald, Rachel Dannay, Sharon R. Lewin, Rachele M. Bochart, Michael Nekorchuk, Louis J. Picker, Jeremy Smedley, Michael Hull, Danica Shao, Benjamin D. Varco-Merth
article en
2 citations

Abstract

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 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.

PLoS PathogensVol. 20(8)
Oregon National Primate Research Center (US), The Royal Melbourne Hospital (AU), Oregon Health & Science University (US), The University of Melbourne (AU), UNSW Sydney (AU), Fred Hutch Cancer Center (US), Peter Doherty Institute (AU), Frederick National Laboratory for Cancer Research (US), Monash University (AU)
U.S. Department of Health and Human Services, Sanofi, Gilead Sciences, ViiV Healthcare, Frederick National Laboratory for Cancer Research, National Institutes of Health, Oregon National Primate Research Center, Sanofi Genzyme, Medical Research Council, National Health and Medical Research Council, National Cancer Institute, National Institute of Allergy and Infectious Diseases, Office of Research Infrastructure Programs, National Institutes of Health
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Phagocytosis and Immune Regulation
0.48
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