The
HIV-1 virus has evolved to exploit the human immune system and counteract all
immune defenses mounted against it.
Many different vaccination approaches and therapy treatments have been
attempted to control, eliminate, or prevent HIV-1 infection, however, these
attempts have not proved successful for virus elimination from the body.
One
approach that has been used to combat HIV-1 infection is the use of ART, or
antiretroviral therapy, and this approach has proven to be effective at
reducing viral levels in the blood.
ART suppresses HIV-1 viremia to undetectable levels within 12-48 weeks
in a majority of patients. This
therapy is a “cocktail” or combination therapy of three or more drugs,
including 2 nucleoside-based
reverse transcriptase inhibitors (prevents production of the virus genome by
inhibiting RNAàDNA
transcription), and one or more of the following drugs: non-nucleoside reverse
transcriptase inhibitors, membrane fusion inhibitors, viral protease
inhibitors, or integrase inhibitors.
Each of these drugs targets a specific part of the viral lifecycle,
making it unable to replicate and infect other cells. Because each drug is mutually exclusive and targets a
different area of the lifecycle, it is unlikely that a virus will develop
resistance to all three drugs.
Therefore, because the virus does not produce escape mutants from the
therapy, this approach is effective at reducing viral levels in the blood (ART
information) (more on ART)
However, by the time ART is put into effect, the virus has already established
residence in T cells in the body, and can continue to infect other cells
undetected by the drug by avoiding exposure in the blood via direct
cell-to-cell infection. Another
problem with the use of ART for HIV-1 treatment is that it must be administered
indefinitely, and if it is discontinued, there is a rapid rebound of viremia,
or viral infection of the blood. Taking
ART indefinitely is undesired due to negative side effects (common
ART side effects) and resistance to the drugs that develops overtime due to
mutation.
Another
approach to combat HIV-1 infection has been the use of monoclonal neutralizing
anti-HIV-1 antibodies, however, in the past, these antibodies have proven to be
ineffective at controlling infection of humanized mice (hu-mice) (Hu-mice as the murine model
for the analysis of human hematolymphoid differentiation and function). However, as of late, more potent
antibodies have been uncovered that have decreased viremia in hu-mice and have
longer half lives. Antibodies that
target gp120 glycoprotein in the HIV viral envelope have been studied as a
potential means of neutralizing HIV infection. Gp120 binds to CD4 on T cells, enabling initial viral-cell
contact before membrane fusion and insertion of the viral genome (more on gp120).
In
a recent study conducted by Horwitz et al (2013) (published in the Proceedings
of the National Academy of Sciences of the USA: HIV-1 Suppression and durable
control by combining single broadling neutralizing antibodies (bNAbs) and
antiretroviral drugs in humanized mice), three antibodies targeting different
epitopes of gp120 were used in combination with ART and the effects were
analyzed. The three antibdies were
3BNC117 (a potent CD4 binding site antibody with a long half life), PG16 (which
recognizes the V1/V2 loop region), and 10-1074 (which targets the base of the
V3 stem).
First,
HIV-1 infected mice were treated with all three antibodies for 6 weeks, 2-3
weeks after infection, and viral loads were monitored by quantifying RT
(reverse transcriptase). They also
measured the total HIV-1 DNA in human lymphoid cells. All mice showed rapid and continuous viral load suppression,
as well as decreased cellular HIV-1 DNA.
It was concluded that combined immunotherapy with all three antibodies
was sufficient to control plasma HIV-1 RNA levels and cellular HIV-1 DNA levels
in hu-mice.
Next,
they tested whether or not these highly potent bNAbs could prolong the
suppression of HIV-1 in mice treated with ART, and whether immunotherapy could
prevent viral rebound after stopping ART.
Mice were treated for 3 weeks with ART, then they were given a bNAb
trimixture, and continued the immunotherapy for 4 weeks after ART
termination. Mice that were given
the bNAb therapy did not have viral rebound after ending ART, unlike mice
treated with ART alone, who experienced rapid viral rebound upon stopping
treatment. To see if the viremic
control after stopping ART was due to the antibodies, authors obtained gp120
sequences from mice, which demonstrated that although some clones had developed
resistance to one of the three antibodies, no gp120 clones showed resistance to
all three antibodies! Therefore,
it was concluded that the potent bNAb trimix protected against rebound after
ART was discontinued.
The
research team next tried to determine whether a single bNAb could prevent
against viral rebound when viral load was initially suppressed with ART. They administered ART, added one of the
bNAbs being studied, and after 3-4 weeks, terminated ART while continuing
monoclonal Ab therapy alone. The
infection remained controlled in 50-86% of mice, whereas it rebounded quickly
in those without any monoclonal therapy.
Next, they sought to determine whether the viral escape from monoclonal
Abs was due to specific mutations in the Env gene of HIV-1, the gene that
encodes the gp120 protein. The
authors cloned and sequenced gp120 from HIV-infected mice that had rebounded
the drug after or during immunotherapy, and found that sequences from mice that
rebounded during therapy had specific mutations that made them
antibody-resistant, whereas mice that rebounded after immunotherapy had no antibody-resistant
mutations, and remained sensitive to neutralization by antibodies.
This
study shows that bNAbs may alleviate some of the burdens associated with
lifelong treatment of ART because of their longer half-lives, ability to
eliminate infected cells, and ability to control viremia after ART
termination. Future studies may
look into the potential side effects of long term administration of bNAb
immunotherapy, as well as the discovery of other bNAbs that could prove
successful in controlling HIV-1 infection. The trimixture-immunotherapy combined with ART should be
tested in clinical, human trials to see if it has an effect on the patient
progression to AIDS or lifespan of HIV-1 infected individuals.
Primary Sources:
Horwitz J.A., Halper-Stromberg A.,
Mouquet H., Gitlin A.D., Tretiakova A., Eisenreich T.R., Malbec M., Gravemann
S., Billerbeck E., Dorner M., Büning H., Schwartz O., Knops E., Kaiser R.,
Seaman M.S., Wilson J.M., Rice C.M., Ploss A., Bjorkman P.J., Klein F.,
Nussenzweig M.C. (2013) HIV-1 suppression and durable control by combining
single broadly neutralizing antibodies and antiretroviral drugs in humanized
mice. Proc Natl Acad Sci USA 110:16538-16543.
Other sources:
No comments:
Post a Comment