The central obstacle to curing HIV is the latent reservoir: a population of CD4-expressing cells carrying transcriptionally silent but intact proviruses. Antiretroviral therapy (ART) suppresses plasma viraemia indefinitely but does not touch these cells. Cells with actively expressed provirus can be attacked by broadly neutralizing antibodies, but latently infected cells expose no viral proteins and therefore cannot be selectively targeted without first forcing the virus out of hiding. To date, the only interventions that have convincingly eliminated the reservoir are cytotoxic conditioning regimens and allogeneic stem-cell transplantation from donors carrying the CCR5-Δ32 mutation, which renders the receptor non-functional and blocks entry of most HIV strains.

Previous early-treatment experiments in macaques have been uniformly disappointing. When ART was initiated three or seven days after SIV or SHIV infection, no animals achieved remission. In one large study using a low-dose intravenous inoculum designed to model slow human transmission, only one of thirteen animals treated six days after infection failed to rebound, and none treated at seven days did. Even allogeneic stem-cell transplantation in Mauritian cynomolgus macaques, which can produce cure, is sometimes defeated by viral spread to engrafting CCR5-positive donor cells. The new study therefore asked a different question: rather than relying on ART alone, could the cells that harbour and sustain the early reservoir be physically removed?

The experimental design was deliberately aggressive. Twenty-five newborn rhesus macaques were randomized at birth, and at roughly two to three weeks of age they received a high oral dose of SIVmac251, a highly pathogenic and genetically heterogeneous swarm virus. The animals were left untreated for seven days to allow a permanent, systemic infection to establish, then placed on a triple antiretroviral regimen of tenofovir, emtricitabine and dolutegravir. Two days after ART initiation, one group continued on ART alone, a second received a CD4-depleting antibody called CD4R1, and a third received a single intravenous dose of an anti-CCR5/CD3 bispecific antibody, a molecule engineered to bind CCR5 on target cells and CD3 on T cells, thereby recruiting T cells to destroy any cell expressing CCR5. ART was withdrawn after eighteen weeks and viral rebound was monitored.

Twenty of the twenty-five infants were successfully infected, and all infected animals showed unambiguous systemic SIV infection with repeated plasma viral-load detections and cell-associated viral RNA. Both depleting antibodies accelerated the decline in plasma viraemia compared with ART alone, with statistically significant steeper slopes of decay in both antibody groups. The team also tracked cell-associated SIV DNA before and after depletion: control animals showed an average drop of 1.7 log units, CD4R1 recipients 2.7 log units, and bispecific antibody recipients 3.4 log units, a statistically significant advantage for the CCR5-targeting strategy. Notably, about ninety-five percent of proviruses detected during this early phase were intact, meaning the measured depletion applied to the replication-competent fraction of the reservoir rather than defective debris.

The immunological consequences of the two antibodies differed in instructive ways. CD4R1 produced profound and durable depletion of CD4-positive T cells and monocytes, with deficits persisting in some animals for twelve weeks. The bispecific antibody first caused a temporary CD3-positive lymphopenia that resolved within about four weeks, followed by a remarkably specific and long-lasting loss of CCR5-expressing cells. Circulating CCR5-positive memory CD4 and CD8 T cells were essentially eliminated, with three or fewer CCR5-positive CD4 memory cells per millilitre of blood detected for at least fourteen weeks after a single administration, and relative depletion persisting in some animals for thirty-four weeks or longer. Multiplex cytokine assays showed no significant inflammatory response attributable to the treatment, and the animals tolerated the procedure well, gaining weight comparably to controls, with only mild, transient hypersensitivity-type reactions in a few individuals.

The virological outcomes after ART withdrawal were striking. Every control animal rebounded within seven days, and six of eight CD4R1-treated animals rebounded within the same window. Among the seven bispecific antibody recipients, the first two rebounds did not occur until thirteen days after treatment interruption. Four others delayed rebound to ninety-seven or one hundred seventy-three days, or never rebounded at all during follow-up, which extended to twenty-nine weeks in one case and four years in another. A Cox proportional hazards model incorporating peak viral load and treatment group showed that both lower peak viraemia and bispecific antibody treatment independently delayed rebound, with the model estimating a ninety-five percent reduction in rebound hazard attributable to the bispecific antibody. Inheritance of protective MHC alleles did not predict outcome.

To determine whether the non-rebounding animals had truly cleared the virus, the researchers subjected three animals in durable remission to a battery of the most demanding tests available. High-sensitivity quantitative PCR with a detection limit of four copies per millilitre found no residual viraemia. The animals were then depleted of CD8-positive T cells with a rhesusized anti-CD8 antibody to remove any cytotoxic T lymphocyte control that might be suppressing hidden virus; rebound still did not occur, indicating that CD8 cells were not the mechanism of remission. Two of the animals were necropsied, and bone marrow, intestine, lung, spleen and multiple lymph nodes were examined by qPCR and by RNAscope and DNAscope in situ hybridization. No viral RNA or DNA was detected in any tissue, in sharp contrast to a viraemic control animal in which all six tissues tested were positive. Viral outgrowth assays from lymph-node cells failed to recover SIV in eight of eight attempts involving tens of millions of cells.

Mathematical modelling of the rebound data provided a quantitative estimate of how much the reservoir had shrunk. Using statistical tools that integrate viral-load and outgrowth information to infer the rate at which the remaining reservoir produces actively infected cells, the model estimated that CD4R1 treatment was associated with roughly a thirteenfold to twentyfold reduction in reservoir size, while the bispecific antibody was associated with a reduction of roughly 152-fold to 219-fold, after correcting for peak viral load and protective MHC alleles. These figures fall short of the two-thousand-fold reduction that modelling suggests is needed to delay rebound by a year in most people, which points to a second mechanism beyond simple cell killing. The authors argue that removing CCR5-positive cells also strips the virus of the targets it needs: reactivated virions encounter few infectable cells, nascent infectious foci cannot spread, and the residual reservoir decays through viral cytopathicity and cellular attrition. The case of the so-called Chicago patient, who achieved prolonged remission after a CCR5-Δ32 transplant despite a persistent reservoir, supports the idea that ART can be curative when infectable targets are scarce.

Several caveats temper the excitement. The intervention was delivered within days of infection, when the reservoir is small and still dominated by CCR5-positive cells; in chronic infection, the reservoir shifts toward memory and stem-cell-like CD4 subsets whose relationship to CCR5 is weaker, so the strategy may not translate directly to adults with long-standing HIV. The bispecific antibody also depletes CCR5-positive CD8 T cells and other uninfectable cells, raising questions about susceptibility to opportunistic infections, although lifelong CCR5 deficiency in Δ32 homozygotes is generally well tolerated apart from increased risk of symptomatic West Nile virus disease. It is also possible that part of the benefit comes from CCR5 blockade acting as an entry inhibitor rather than from depletion alone. Even so, the study demonstrates for the first time that a pharmacological intervention, a single shot, can achieve meaningful depletion of the replication-competent lentiviral reservoir and produce durable, apparently complete clearance in an animal model. For infants treated very soon after infection, and potentially as a component of combination immunotherapy for older patients, the result reopens a route to HIV cure that many in the field had considered closed.

Subject of Research: Depletion of the SIV reservoir in neonatal macaques using a CCR5/CD3 bispecific antibody

Article Title: SIV reservoir depletion and clearance from neonatal macaques following transient CCR5 depletion

Article References: Deere, J. D., Merriam, D., Machmach, K., Chang, W. L. W., Nekorchuk, M., Méndez-Lagares, G., Kieu, H., Dutra, J., Fontaine, J., Andal, D. R., Sipe, K., Heninger, E., Martin, M., Lu, W., Chin, N., Chen, C., Tran, B. C.-T., Salinas, J., Miller, C. N., … Hartigan-O’Connor, D. J. (2026). SIV reservoir depletion and clearance from neonatal macaques following transient CCR5 depletion. Nature Microbiology. https://doi.org/10.1038/s41564-026-02511-3

Image Credits: AI Generated

DOI: 10.1038/s41564-026-02511-3

Keywords: HIV, SIV, viral reservoir, CCR5, bispecific antibody, macaques, antiretroviral therapy, latent infection, viral rebound, HIV cure, immunotherapy, neonatal infection