SIV clearance from neonatal macaques following transient CCR5 depletion

Abstract

Treatment of people with HIV (PWH) with antiretroviral therapy (ART) results in sustained suppression of viremia, but HIV persists indefinitely as integrated provirus in CD4-expressing cells. Intact persistent provirus, the "rebound competent viral reservoir" (RCVR), is the primary obstacle to achieving a cure. Most variants of HIV enter CD4+ T cells by binding to the chemokine receptor, CCR5. The RCVR has been successfully depleted only in a handful of PWH following cytotoxic chemotherapy and bone marrow transplantation from donors with a mutation in CCR5. Here we show that long-term SIV remission and apparent cure can be achieved for infant macaques via targeted depletion of potential reservoir cells that express CCR5. Neonatal rhesus macaques were infected with virulent SIVmac251, then treated with ART beginning one week after infection, followed by treatment with either a CCR5/CD3-bispecific or a CD4-specific antibody, both of which depleted target cells and increased the rate of plasma viremia decrease. Upon subsequent cessation of ART, three of seven animals treated with CCR5/CD3-bispecific antibody rebounded quickly and two rebounded 3 or 6 months later. Remarkably, the other two animals remained aviremic and efforts to detect replication-competent virus were unsuccessful. Our results show that bispecific antibody treatment can achieve meaningful SIV reservoir depletion and suggest that functional HIV cure might be achievable for recently infected individuals having a restricted reservoir.

Quantitative and Qualitative Distinctions between HIV-1 and SIV Reservoirs: Implications for HIV-1 Cure-Related Studies

“…Within this time window, however, there is considerable variation, and comparing these studies can provide insights into how the variable of ART timing can influence the outcome of cure-related interventions. Very few cure approaches have been evaluated under small, less mature reservoirs that are associated with ART initiation less than 14 days post-infection [ 58 , 59 , 60 , 61 , 62 ]. A subset of these, however, were found to elicit a favorable impact and, in some instances, promote sustained ART-free remission.…”

“…The early ART notwithstanding, a caveat to this study was that it employed a strain of hybrid simian–human SIV (SHIV-SF162P3), many of which have variable replicative capacity and pathogenicity in vivo [ 63 ]. A more recent study employing wild-type SIVmac251 in neonatal macaques administered ART 7 dpi concurrently with a CCR5/CD3- or CD4-specific antibody had the goal of stimulating the clearance of target cells [ 59 ]. Upon interruption of ART, plasma SIV in three out of seven animals rebounded quickly, in two out of seven, rebound was delayed by 3 and 6 months, and in the remaining two, sustained remission was observed up to greater than 3 years post-ART cessation [ 59 ].…”

“…A more recent study employing wild-type SIVmac251 in neonatal macaques administered ART 7 dpi concurrently with a CCR5/CD3- or CD4-specific antibody had the goal of stimulating the clearance of target cells [ 59 ]. Upon interruption of ART, plasma SIV in three out of seven animals rebounded quickly, in two out of seven, rebound was delayed by 3 and 6 months, and in the remaining two, sustained remission was observed up to greater than 3 years post-ART cessation [ 59 ]. The remarkable outcomes of these two studies suggest two exciting possibilities.…”