Depletion of Gut-Resident CCR5⁺Cells for HIV Cure Strategies

Abstract

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.

SIV clearance from neonatal macaques following transient CCR5 depletion

“…2; depletion of cells from tissues is addressed in ref. 14). Therefore, the RCVR-depleting agents tested here had surprisingly long-lasting effects on blood and tissue immunophenotypes but, importantly, bsAb treatment did not result in acute inflammatory cytokine production or persistent lymphopenia.…”

“…Mathematical modeling suggests that a 2,000-fold reduction in the reservoir is required to delay rebound by one year in the majority of treated people, 16,17 while a 5,000-fold reduction is required for a 50% chance of sustaining remission for three years. An efficiency of depletion of even 99.9% in peripheral blood and less in tissues 14 would seem unequal to the task. One possibility is that CCR5 depletion alters key parameters that control viral rebound, such as the rate at which virus from reactivated cells can infect of other targets, or even the likelihood of reactivation from latency.…”

“…Two days after ART initiation, two groups were administered candidate RCVR-depleting therapies: group B received the depleting anti-CD4 antibody, CD4R1, while group C received an anti-CD3/CCR5 bsAb previously described by our group to deplete CCR5 + cells. 14 ART was withdrawn after 18 weeks and viral rebound was subsequently monitored.…”

Bispecific antibody-derived molecules to target persistent HIV infection

“…A bispecific antibody with anti-rhesus CCR5 and anti-rhesus CD3 specificities and rhesus IgG1 constant regions was constructed by a Fab arm exchange method. 62 This molecule is monovalent for each specificity. When administered to rhesus monkeys, CCR5+ cells were depleted from blood and colon biopsy samples, which remained depleted in blood for at least 1 week, but returned to pretreatment levels in colon biopsies within 1 week.…”