Transmission of simian immunodeficiency virus SIVcpz and the evolution of infection in the presence and absence of concurrent human immunodeficiency virus type 1 infection in chimpanzees.

Current data suggest that the human immunodeficiency virus type 1 (HIV-1) epidemic arose by transmission of simian immunodeficiency virus (SIV) SIVcpz from a subspecies of common chimpanzees (Pan troglodytes troglodytes) to humans. SIVcpz of chimpanzees is itself a molecular chimera of SIVs from two or more different monkey species, suggesting that recombination was made possible by coinfection of one individual animal with different lentiviruses. However, very little is known about SIVcpz transmission and the susceptibility to lentivirus coinfection of its natural host, the chimpanzee. Here, it is revealed that either infected plasma or peripheral blood mononuclear cells readily confer infection when exposure occurs by the intravenous or mucosal route. Importantly, the presence of preexisting HIV-1 infection did not modify the kinetics of SIVcpz infection once it was established by different routes. Although humoral responses appeared as early as 4 weeks postinfection, neutralization to SIVcpz-ANT varied markedly between animals. Analysis of the SIVcpz env sequence over time revealed the emergence of genetic viral variants and persistent SIVcpz RNA levels of between 10(4) and 10(5) copies/ml plasma regardless of the presence or absence of concurrent HIV-1 infection. These unique data provide important insight into possible routes of transmission, the kinetics of acute SIVcpz infection, and how readily coinfection with SIVcpz and other lentiviruses may be established as necessary preconditions for potential recombination.

T-cell activation and B-cell depletion in chimpanzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody construct.

BscCD19xCD3 is a bispecific single-chain antibody construct with exceptional cytotoxic potency in vitro and in vivo. Here, we have investigated the biological activity of bscCD19xCD3 in chimpanzee, the only animal species identified in which bscCD19xCD3 showed bispecific binding, redirected B-cell lysis and cytokine production comparable to human cells. Pharmacokinetic analysis following 2-h intravenous infusion of 0.06, 0.1 or 0.12 mug/kg of bscCD19xCD3 as part of a dose escalation study in a single female chimpanzee revealed a half-life of approximately 2 h and elimination of the bispecific antibody from circulation within approximately 8 h after the end of infusion. This short exposure to bscCD19xCD3 elicited a transient increase in serum levels of IFNgamma, IL-6, IL-2, soluble CD25, and transiently upregulated expression of CD69 and MHC class II on CD8-positive cells. Cytokine release and upregulation of T-cell activation markers were not observed with vehicle controls. A multiple-dose study using 5 weekly doses of 0.1 mug/kg in two animals also showed transient cytokine release and an activation of peripheral T cells with a first-dose effect, accompanied by a transient lymphopenia. While oscillations of T-cell counts were relatively even during repeated treatments, the amplitudes of peripheral B cells declined with every infusion, which was not observed in a vehicle control animal. Our data show that bscCD19xCD3 can be safely administered to chimpanzees at dose levels that cause fully reversible T-cell activation and, despite a very short exposure time, cumulative loss of peripheral B lymphocytes. A clinical trial testing prolonged administration of bscCD19xCD3 (MT103) for improving efficacy is currently ongoing.