The HIV reservoir forming at the earliest stages of infection is likely composed of CCR5 cells, because these cells are the targets of transmissible virus. Restriction of the CCR5 reservoir, particularly in the gut, may be needed for subsequent cure attempts. Strategies for killing or depleting CCR5 cells have been described, but none have been tested in vivo in nonhuman primates, and the extent of achievable depletion from tissues is not known. In this study we investigate the efficacy of two novel cytotoxic treatments for targeting and eliminating CCR5 cells in young rhesus macaques. The first, an immunotoxin consisting of the endogenous CCR5 ligand RANTES fused with Pseudomonas exotoxin (RANTES-PE38), killed CCR5 lamina propria lymphocytes (LPLs) ex vivo, but had no detectable effect on CCR5 LPLs in vivo. The second, a primatized bispecific antibody for CCR5 and CD3, depleted all CCR5 cells from blood and the vast majority of such cells from the colonic mucosa (up to 96% of CD4CCR5). Absence of CCR5-expressing cells from blood endured for at least 1 week, while CCR5 cells in colon were substantially replenished over the same time span. These data open an avenue to investigation of combined early ART treatment and CCR5 reservoir depletion for cure of HIV-infected infants.
The contribution of the host immune system to efficacy of new anti-hepatitis C virus (HCV) drugs is unclear. We undertook a longitudinal, prospective study of 33 individuals with chronic HCV treated with combination PEG-interferon-ɑ, ribavirin, and telaprevir/boceprevir. We characterized innate and adaptive immune cells to determine if kinetics of the host response could predict sustained virologic response (SVR). We show that characteristics of the host immune system present before treatment were correlated with successful therapy. Augmentation of adaptive immune responses during therapy was more impressive among those achieving SVR. Most importantly, active memory T-cell proliferation before therapy both predicted SVR and was associated with the magnitude of HCV-specific responses at week 12 after treatment start. After therapy initiation, the most important correlate of success was minimal monocyte activation, as predicted by previous in vitro work. In addition, subjects achieving SVR had increasing expression of the transcription factor, T-bet, a driver of Th1 differentiation and cytotoxic effector cell maturation. These results show that host immune features present before treatment initiation predict both SVR and eventual development of a higher frequency of functional virus-specific cells in blood. Such host characteristics may also be required for successful vaccine-mediated protection.
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