CD4 reconstitution and reduction of reservoir in HIV-positive patients following a single infusion of CCR5 modified autologous CD4 T cells (SB-728-T)

Abstract

BackgroundSB-728-T is a zinc finger nuclease-mediated, CCR5-modified, autologous CD4 T-cell product. We investigated whether CCR5 knockout might render a survival advantage to the gene-modified CD4 T cells in HIV-infected patients and potentially improve antiviral immune function. MethodsNine aviraemic and chronically HIV-infected patients with suboptimum CD4 counts (200–500 cells per μL) were infused with 10–30 billion SB-728-T cells. The treated patients were male (seven white, two Hispanic) with an average age of 49 years (SD 6·5), and 20·8 years (SD 6·5) of diagnosed HIV infection. All participants were on antiretroviral therapy before the study and for the duration of the study. FindingsWe observed that a single infusion of SB-728-T was well tolerated and led to short-term and long-term CD4 reconstitution, with a median increase of 223 cells (95% CI 79–688) at day 14 and 103 cells (14–368) at month 12. This was primarily driven by an increase in central memory CD4 T cells (TCM) (r=0·9, p=0·083). CD4 reconstitution also correlated with reduced inflammation in the innate immune system, whereby patients who showed comparatively less improvement in CD4 cell counts had overexpression of activation markers, as well as a gene expression signature of upregulated genes downstream of the type II interferon pathway. CCR5-modified CD4 T cells peaked near day 14 (median 8·5% CCR5-modified allele of peripheral CD4 T cells; 95% CI 5·2–12·0) and were sustained for longer than 12 months (median 4·8% [3·1–8·0] at 6 months; and 5·6% [3·3–8·8] at 12 months). By contrast, CCR5 modification was maintained specifically in the central memory T-cell compartment (median 6%, 7%, and 8% at approximately 15 days, 6 months, and 12 months, respectively). At month 12, we observed reductions in total cell-associated HIV DNA concentrations using digital droplet PCR and longitudinal linear regression analysis (median −0·6 log HIV copies per 106 peripheral blood mononuclear cells [95% CI −0·03 to −0·9]) which were related to both CD4 reconstitution (r=−0·86, p=0·024) and exposure to CCR5-modified cells (r=-0·75, p=0·002). InterpretationSB-728-T infusion is safe and is associated with sustained improvements in CD4 cell counts. Decreased inflammation might provide a survival advantage after the infusion of central memory CD4 T cells. SB-728-T could have a role in the observed decrease in latent reservoir size. Clinically robust techniques such as digital droplet PCR for quantification of HIV in peripheral blood mononuclear cells are useful to guide clinical assessment of the antiviral effect of interventions in aviraemic HIV patients who are well controlled on antiretroviral therapy. FundingThis research was supported by funding to R-PS from the National Institutes of Health(U19 AI096109-03) and amfAR.