New anti-HIV antibody function discovered: Tethering of viral particles
at the surface of cells

Date:
February 3, 2022
Source:
Institut Pasteur
Summary:
Researchers have discovered a new function of anti-HIV-1 antibodies
by applying cutting-edge microscopy techniques to in vitro viral
cultures.

The scientists found that certain antibodies already known for
effectively targeting HIV-1 envelope (Env) protein can prevent
infected cells from releasing viral particles, thus halting
viral spread. The findings demonstrate that these powerful
antibodies exhibit different antiviral activities in addition
to neutralization.



FULL STORY ========================================================================== Teams at the Institut Pasteur, CNRS, Vaccine Research Institute (VRI)
and Universite' de Paris have discovered a new function of anti-HIV-1
[1] antibodies by applying cutting-edge microscopy techniques to in
vitro viral cultures. The scientists found that certain antibodies
already known for effectively targeting HIV-1 envelope (Env) protein can prevent infected cells from releasing viral particles, thus halting viral spread. The antibodies are Y-shaped, enabling them to attach themselves
between the infected cell and viral particles or directly between viral particles. This chain composed of antibodies and viral particles prevents
viral spread. These findings demonstrate that these powerful antibodies
exhibit different antiviral activities in addition to neutralization. The
study is published in the February 2, 2022 issue of Nature Communications.


========================================================================== Broadly neutralizing antibodies (bNAbs) targeting virus envelope
(Env) protein have significant potential for treating HIV-1. They were initially identified in rare cases of patients whose serum was capable
of inhibiting numerous HIV strains. These antibodies exhibit multiple
antiviral activities. As well as neutralizing the virus, i.e. preventing
it from infecting new cells, they also kill infected cells. Consequently,
they are referred to as polyfunctional molecules. It is necessary to
fully understand the scope of these antiviral activities in order to use existing antibodies more effectively or refine the selection criteria
for new antibodies. It is moreover useful to further investigate the polyfunctionality of anti-HIV-1 antibodies in order to improve our understanding of the role played by antibodies and thus tackle other
viral infections.

Initially, teams at the Institut Pasteur, CNRS, VRI and Universite' de
Paris sought to determine whether antibodies were capable of preventing infected cells from producing viral particles. To that end, they cultured
CD4 T cells (HIV's natural target) in vitro with various antibodies for
24 hours. They subsequently measured the quantity of viral particles
produced by the cells in the culture medium and the quantity of viral
particles remaining in the cells.

As a result of these experiments, the scientists were able to demonstrate
that certain antibodies increased virus quantity in cells but reduced
it in the culture medium. This intriguing finding led them to believe
that certain antibodies impeded the release of viral particles without preventing their production.

To test this theory, the scientists used various microscopy techniques
to observe cells' production of viral particles. They initially examined
the cells by fluorescence microscopy, a technique used to differentiate
virus proteins.

This enabled them to demonstrate that infected cells accumulate large quantities of mature viral protein. This finding suggests that full
viral particles accumulate in cells. To determine the precise location of
these viral particles, the scientists subsequently used scanning electron microscopy to observe the surface of infected cells. "Using this method,
we observed that these antibodies (bNAbs) prompt an accumulation of
viral particles at the surface of cells, forming clusters and highly
atypical structures (see illustration)," comments Timothe'e Bruel,
co-last author of the study and scientist in the Virus and Immunity Unit
[2] at the Institut Pasteur.

Next, the scientists combined a transmission electron microscopy
technique with immunogold labeling. This enabled them to demonstrate that antibodies interpose themselves between viral particles and the infected
cell, forming a chain cluster. Experiments with mutant antibodies
subsequently demonstrated that the antibodies' Y shape creates this
clustered structure. Their arms are capable of linking two viruses,
or one virus to the infected cell membrane, and their attachment points
are sufficiently strong to prompt this phenomenon.

"We have demonstrated that only the most powerful antibodies tether viral particles at the surface of infected cells. Trapped viral particles can
no longer infect new cells," concludes Olivier Schwartz, co-last author of
the study and Head of the Virus and Immunity Unit at the Institut Pasteur.

This work has revealed a new antiviral activity for broadly neutralizing
anti- HIV-1 antibodies. It deepens our understanding of these antibodies' mechanism of action and explains their efficacy in clinical trials. The scientists are now examining antibodies targeting other viruses, including SARS-CoV-2, to determine whether they also inhibit viral spread through
this mechanism.

Notes: [1] HIV-1 is the pandemic form of the human immunodeficiency
virus. The other less common type is HIV-2.

[2] This is named the "Virology Unit" at the CNRS (CNRS/Institut Pasteur).

========================================================================== Story Source: Materials provided by Institut_Pasteur. Note: Content may
be edited for style and length.


========================================================================== Journal Reference:
1. Je're'my Dufloo, Cyril Planchais, Ste'phane Fre'mont, Vale'rie
Lorin,
Florence Guivel-Benhassine, Karl Stefic, Nicoletta Casartelli,
Arnaud Echard, Philippe Roingeard, Hugo Mouquet, Olivier Schwartz,
Timothe'e Bruel. Broadly neutralizing anti-HIV-1 antibodies
tether viral particles at the surface of infected cells. Nature
Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-28307-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220203122511.htm

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