The neuroinvasive profiles of H129 (herpes simplex virus type 1) recombinants with putative anterograde-only transneuronal spread properties

Abstract

The use of viruses as transneuronal tracers has become an increasingly powerful technique for defining the synaptic organization of neural networks. Although a number of recombinant alpha herpesviruses are known to spread selectively in the retrograde direction through neural circuits only one strain, the H129 strain of herpes simplex virus type 1, is reported to selectively spread in the anterograde direction. However, it is unclear from the literature whether there is an absolute block or an attenuation of retrograde spread of H129. Here we demonstrate efficient anterograde spread, and temporally delayed retrograde spread, of H129 and three novel recombinants. In vitro studies revealed no differences in anterograde and retrograde spread of parental H129 and its recombinants through superior cervical ganglion neurons. In vivo injections of rat striatum revealed a clear bias of anterograde spread, although evidence of deficient retrograde transport was also present. Evidence of temporally delayed retrograde transneuronal spread of H129 in the retina was observed following injection of the lateral geniculate nucleus. The data also demonstrated that three novel recombinants efficiently express unique fluorescent reporters and have the capacity to infect the same neurons in dual infection paradigms. From these experiments we conclude that H129 and its recombinants efficiently infect neurons through anterograde transneuronal passage, but also are capable of temporally delayed retrograde transneuronal spread. In addition, the capacity to produce dual infection of projection targets following anterograde transneuronal passage provides an important addition to viral transneuronal tracing technology.

Anterograde monosynaptic transneuronal tracers derived from herpes simplex virus 1 strain H129

“…In consistence with previous reports [2, 6, 11], H129-G4 efficiently transmitted anterogradely from the retina, labeled LGN and downstream brain regions (Additional file 4: Figure S4). LGN directly projects to layer IV of primary visual cortex (V1) [20], and GFP signal was indeed observed at this layer when H129-G4 was injected in to LGN.…”

Transsynaptic tracing and its emerging use to assess graft-reconstructed neural circuits

“…Polysynaptic tracing therefore allows for a degree of agnosticism as to how functional host‐graft circuits could be arranged anatomically, albeit with increased uncertainty as to which host and graft neurons are directly connected. For example, the H129 strain of HSV spreads polysynaptically, primarily in the anterograde direction, and has been used to identify graft neurons that are downstream of cortical neurons . The Bartha strain of pseudorabies virus has similarly been used to identify graft neurons upstream of phrenic motor neurons .…”

Transneuronal Circuit Analysis with Pseudorabies Viruses

“…However, it is useful to note that methods relevant to the generation and use of Herpes Simplex Virus (HSV), the human pathogen, are in large part the same as those detailed for PRV. Additionally, the H129 strain of HSV is the only known alphaherpesvirus that is transported largely, but not exclusively, in the anterograde direction (Zemanick et al, 1991; Barnett et al, 1995; Archin and Atherton, 2002; Archin et al, 2003; Kelly and Strick, 2003; Rinaman and Schwartz, 2004; Song et al, 2009; Lo and Anderson, 2011; McGovern et al, 2012a,b; Vaughan and Bartness, 2012) through circuits, and we illustrate new recombinants of H129 that express unique reporters (Wojaczynski et al, 2014). …”