One of the most efficient means by which HIV spreads between
cells is by promoting cell to cell contacts. The virus is then transferred from
infected to uninfected cell via what has been dubbed a “virological synapse.”
Some prior studies have raised the concern that this process may be invulnerable to
approaches designed to inhibit viral entry into cells, including neutralizing
antibodies and entry inhibitor drugs. A new study published in the Journal of
Virology offers some reassurance that this is not in fact the case. The
researchers show that a variety of entry inhibitors both big (in the form of
the monoclonal antibody b12) and small (the CCR5-blocking entry inhibitor
compound TAK-779) remain capable of inhibiting infection in the setting of CD4
T cell to CD4 T cell transfer. They suggest prior results may have been
misleading due to problems with the readout used to assess infection, and
state: “these results are encouraging for use of prophylactic vaccines designed
to elicit neutralizing antibodies and for entry inhibitors applied in a
prophylactic or therapeutic setting.” There is, however, a caveat in that the
results may not apply to other cell types such as macrophages, and the
researchers note that some relatively recent data has indicated that transfer of HIV
between dendritic cells and CD4 T cells may be resistant to inhibition by
neutralizing antibodies. The paper is accompanied online by supplemental videos showing contacts between infected (red) and uninfected (green)
cells (video S1) and visualizing the synapse in the context of both X4-using (video S2) and R5-using (video S3) HIV isolates.
Journal of Virology, April 2010, p. 3516-3527, Vol. 84, No.
7
doi:10.1128/JVI.02651-09
Nicola Martin,1 Sonja Welsch,2,4 Clare Jolly,3 John A. G.
Briggs,4 David Vaux,1 and Quentin J. Sattentau1
The Sir William Dunn School of Pathology, University of
Oxford, Oxford OX1 3RE, United Kingdom,1 Structural Biology Unit, Wellcome
Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United
Kingdom,2 Wohl Virion Centre and MRC/UCL Centre for Medical Molecular Virology,
University College London, London W1T 4JF, United Kingdom,3 Structural and
Computational Biology Unit, European Molecular Biology Laboratory, D-69117
Heidelberg, Germany4
Human immunodeficiency virus type 1 (HIV-1) can disseminate
between CD4+ T cells via diffusion-limited cell-free viral spread or by
directed cell-cell transfer using virally induced structures termed virological
synapses. Although T-cell virological synapses have been well characterized, it
is unclear whether this mode of viral spread is susceptible to inhibition by
neutralizing antibodies and entry inhibitors. We show here that both cell-cell
and cell-free viral spread are equivalently sensitive to entry inhibition.
Fluorescence imaging analysis measuring virological synapse lifetimes and
inhibitor time-of-addition studies implied that inhibitors can access preformed
virological synapses and interfere with HIV-1 cell-cell infection. This concept
was supported by electron tomography that revealed the T-cell virological
synapse to be a relatively permeable structure. Virological synapse-mediated
HIV-1 spread is thus efficient but is not an immune or entry inhibitor evasion
mechanism, a result that is encouraging for vaccine and drug design.
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