The Vpu protein of the HIV virus makes it harder for antibodies to recognize infected cells

During HIV infection, several types of antibodies (Abs) play different roles
.
Broadly neutralizing antibodies (bNAbs) can recognize the conformation of envelope proteins—as the only viral antigen exposed to virions and infected cells, which are prime targets for humoral reactions—but they are difficult to induce
in vivo.
Non-neutralizing antibodies (nnAbs), most antibodies in the plasma of HIV-1 infected people, are readily produced by vaccination and are considered a potential alternative
.
In addition, nnAbs have been shown to eliminate HIV-1-infected cells through antibody-dependent cytotoxicity (ADCC) and have been confirmed to be protection-related in
vaccine trials.

A Vpu-deficient virus has been used to show that Fc-mediated effector function of nnAbs alters the course of
HIV-1 infection in vivo.
Now, a new study hypothesizes whether the lack of Vpu expression is related to
observed nnAbs activity.
They based on the understanding that Vpu is known to downregulate cell surface CD4, triggering conformational changes
in envelope glycoproteins.

This study, the first to show in humanized mice, shows that the expression of the viral protein Vpu is critical
for infected cells to evade the elimination mechanism known as ADCC.

The work, published in the Cell Reports study, "observed that the modified HIV-1 virus used in certain laboratory experiments did not express Vpu," said Dr.
Andrés Finzi, professor Université de Montréal and researcher
at the CHUM Research Center.
"However, in naturally occurring viruses, this protein actually acts as
a bodyguard for infected cells.
Once expressed, it replicates itself and protects itself
by flying under the radar of the immune system.
”

In fact, the study shows that by expressing Vpuprotein in infected cells, it is much more difficult for non-neutralizing antibodies to recognize these cells in the body
.

Experiments in humanized mice receiving non-neutralizing antibodies confirmed this observation
.
Only animals infected by Vpu that did not express the virus had a decrease in viral load, while the opposite
was true for animals infected by naturally occurring viruses.

More specifically, they found that restoring Vpu expression greatly reduced the infected cells' ability to recognize nnAbs, making them resistant to ADCCs
.
In addition, they write, "The use of nnAbs in humanized mice only lowered the viral load of animals infected with Vpu-deficient virus, not wild-type viruses
.
" "Management of CD4 mimics, known to 'turn on' Env and expose the nnAb epitope, sensitizes wild-type viruses to nnAb Fc effector function
.
"

In 2013, Finzi's team demonstrated that infected cells are not affected by the ADCC response because the viral envelope remains closed
under the action of Vpu and the protein Nef, the second bodyguard.
Because they are adequately protected, infected cells cannot be detected
by nearby antibodies.

Finzi said: "In the lab, if Vpu is not expressed in the virus you use, the envelope of the infected cell opens
.
If there is no protection, it will be attacked
by antibodies.
This may explain some of the surprising results
reported by non-neutralizing antibodies.
In real life, HIV is always on alert thanks to two bodyguards, Vpu and Nef
.
”

The researchers believe that this work highlights the importance of Vpu-mediated evasion of humoral responses and should be considered
in the development of future HIV-1 vaccines and strategies to eradicate the virus.

According to the World Health Organization, more than 38 million people were infected with the virus
that causes HIV by the end of 2021.