Extensive CD8β depletion does not prevent control of viral replication or protection from challenge in macaques chronically infected with a live attenuated simian immunodeficiency virus

Abstract

word count: 249) 21 We evaluated the contribution of CD8αβ+ T cells on control of live-attenuated simian 22 immunodeficiency virus (LASIV) replication during chronic infection and subsequent protection 23 from pathogenic SIV challenge. Unlike previous reports with a CD8α-specific depleting 24 monoclonal antibody (mAb), the CD8β-specific mAb CD8β255R1 selectively depleted CD8αβ+ 25 T cells without also depleting non-CD8+ T cell populations that express CD8α, such as natural 26 killer (NK) cells and γδ T cells. Following infusion with CD8β255R1, plasma viremia transiently 27 increased coincident with declining peripheral CD8αβ+ T cells. Interestingly, plasma viremia 28 returned to pre-depletion levels even when peripheral CD8αβ+ T cells did not. Although depletion 29 of CD8αβ+ T cells in the lymph node (LN) was incomplete, frequencies of these cells were three-30 fold lower (p=0.006) in animals that received CD8β255R1 compared to control IgG. It is possible 31 that these residual SIV-specific CD8αβ+ T cells may have contributed to suppression of viremia 32 during chronic infection. We also determined whether infusion of CD8β255R1 in the LASIV-33 vaccinated animals increased their susceptibility to infection following intravenous challenge with 34 pathogenic SIVmac239. We found that 7/8 animals infused with CD8β255R1, and 3/4 animals 35 infused with the control IgG, were resistant to SIVmac239 infection. These results suggest that 36 infusion with CD8β255R1 did not eliminate the protection afforded to LASIV vaccination. This 37 provides a comprehensive description of the impact of CD8β255R1 infusion on the immunological 38 composition of the host, when compared to an isotype matched control IgG, while showing that 39 the control of LASIV viremia and protection from challenge can occur even after CD8β255R1 40 administration.41 42 43 Importance: (word count: 124) 44 Studies of SIV-infected macaques that deplete CD8+ T cells in vivo with monoclonal 45 antibodies have provided compelling evidence for their direct antiviral role. These studies utilized 46CD8α-specific mAbs that target both the major (CD8αβ+) and minor (CD8αα+) populations of 47 CD8+ T cells, but additionally deplete non-CD8+ T cell populations that express CD8α, such as 48 NK cells and γδ T cells. In the current study, we administered the CD8β-specific depleting mAb 49 CD8β255R1 to cynomolgus macaques chronically infected with a LASIV to selectively deplete 50 CD8αβ+ T cells without removing CD8αα+ lymphocytes. We evaluated the impact on control of 51 virus replication and protection from pathogenic SIVmac239 challenge. These results underscore 52

Antibody-mediated depletion of select T cell subsets in blood and tissue of nonhuman primates

“…Antibody-mediated depletion has generally been most successful in peripheral blood and more difficult to achieve in tissue (16,32,33). In PBMCs, treatment with MT807R1 or CD8255R1 resulted in the most extensive depletion of targeted cells, followed by treatment with CD4R1, and finally with C207.…”

“…As CD8 is expressed on T and NK cells as either a CD8 homodimer or CD8 heterodimer it is possible to target cells expressing either form by using an anti-CD8 mAb, or those expressing CD8 by using an anti-CD8 mAb (14,15). Targeting CD8 is thought to selectively deplete conventional CD8+ T cells, the vast majority of which express CD8, without depleting donorunrestricted T cells (MAIT, ) or NK cell populations that are thought to express CD8 but not CD8 (16,17). However, the delineation of CD8 and CD8 expression on conventional and donorunrestricted cell subsets is not clear cut, complicating interpretations of CD8 depletion (14,(18)(19)(20)(21).…”