Taking Lessons from the CCR5Δ32 Mutation for Patient Treatment

I’m Lindsay Sween, and welcome to this installment of the AIDS
Pandemic blog and podcast.

Human immunodeficiency virus type 1 (HIV-1) invades a CD4+ (T4)
cell through the attachment of the viral protein gp120 to its
primary cellular receptor, CD4, and to a transmembrane chemokine
coreceptor, usually CCR5 or CXCR4. Agrawal et al. (2007) explain
that the removal of 32 base pairs from the CCR5 gene results in the
CCR5Δ32 mutation, which produces a shortened, nonfunctional protein
that cannot act as a coreceptor due to the fact that it is no
longer expressed on the cell membrane. Thus, individuals homozygous
for the CCR5 mutation (also known as CCR5 -/- individuals) are
extremely resistant to contracting HIV-1, while heterozygous people
(aka CCR5+/- people) express fewer CCR5 proteins on the surface of
their lymphocytes than wild type individuals, which slows the
transition of HIV infection to AIDS. The CCR5Δ32 mutation confers
HIV-1 resistance by two mechanisms: the mutated protein cannot be
expressed on the lymphocyte surface, and it actively downregulates
CXCR4 coreceptor production by causing the formation of
heterodimers between CCR5 and CXCR4 proteins that then get trapped
in the endoplasmic reticulum.

As explained by Nazari and Joshi (2008), individuals with the
CCR5Δ32 mutation appear perfectly healthy in all other areas of
their immune systems, which seems to indicate that the CCR5
chemokine receptor is not absolutely essential for immune function.
Thus, with no selective pressure against the CCR5Δ32 mutation,
Agrawal et al. (2007) report that Caucasians carry the mutation
relatively frequently, with about 1% of individuals being
homozygous for the mutated allele and approximately 10% of the
population being heterozygous. Individuals of purely African or
Asian descent, however, almost entirely lack the CCR5Δ32
mutation.


Figure 1. The CCR5Δ32 mutation results in a nonfunctional protein
that cannot serve as a cell surface coreceptor for M-tropic (aka
CCR5-tropic or R5) HIV viral isolates and, thus, confers some
resistance to HIV-1 infection. The immune cells are still fully
receptive to T-tropic (aka CXCR4-tropic or X4) viral isolates,
which could bind to their coreceptor, CXCR4 (aka fusin), and
transmit HIV-1 infection.
From: Samson, Michel. “Human immunodeficiency virus (HIV).” Access
Science Online.
McGraw-Hill.
.

There is now a new antiretroviral drug called maraviroc, which was
approved by the U.S. Food and Drug Administration U.S. Food and
Drug Administration in August 2007 and mimics the natural CCR5Δ32
mutation by acting as an antagonist for the CCR5 receptor and
preventing the viral envelope protein gp120 from binding to it.
Lieberman-Blum et al. (2008) report the results of two Phase
IIb/III clinical trials, MOTIVATE 1 and 2, in which the effects of
treatment with 300 mg of maraviroc once or twice daily were
compared to placebo treatment in patients who were already being
treated with HAART and still had primarily R5 HIV-1 infection.
Maraviroc was found to decrease viral load by a greater percentage
than placebo. Of the patients receiving maraviroc once or twice
daily, 43.2% and 45.5%, respectively, had virus particle counts of
less than 50 copies per milliliter, as opposed to 16.7% of patients
in the placebo group. After the 48 weeks of the studies, patients
demonstrated average viral load reductions of -1.68 log10 copies/mL
for the once daily group and -1.84 log10 copies/mL for the twice
daily group compared to -0.78 log10 copies/mL for the control
group.


Figure 2. Most patients given maraviroc once or twice daily had
lower HIV-1 viral loads and higher CD4 cell counts at the end of 48
weeks and had a long time period until treatment failure than did
patients taking placebo.
From: Gulick, R.M., Lalezari, J., Goodrich, J., Clumeck, N.,
DeJesus, E., Horban, A., Nadler, J.,
Clotet, B., Karlsson, A., Wohlfeiler, M., Montana, J.B., McHale,
M., Sullivan, J., Ridgway, C., Felstead, S., Dunne, M.W., van der
Ryst, E., Mayer, H. 2008. Maraviroc for Previously Treated Patients
with R5 HIV-1 Infection. The New England Journal of Medicine 359:
1429-1441.

As would be predicted by the absence of adverse health problems in
individuals lacking functional CCR5 receptors due to the CCR5Δ32
mutation, maraviroc produced few severe side effects for the immune
system by blocking the CCR5 surface protein. According to
Lieberman-Blum et al. (2008), 21 of 426 (4.9%) individuals taking
maraviroc and 11 of 209 (5.3%) individuals taking placebo had poor
health outcomes that lead them to stop taking their medication and
quit the trials. Most patients (92.3%) reported at least one side
effect, which included upper respiratory illness, cough, fever, and
abdominal pain. The primary concern with the use of antiretroviral
drugs that block the CCR5 receptor is that the HIV virus will
evolve into X4 or R5X4 variants that will then evade the drug’s
action. For the individuals who were not benefitted by maraviroc,
54.4% of the once-daily patients and 55.2% of the twice-daily
patients demonstrated virus that had changed from the R5 strains to
either X4 or R5X4 strains. When the researchers performed
phylogenetic analyses of the viral envelope proteins in these
strains, however, they found that the new X4 or R5X4 strains had
developed from preexisting viral particles of these strains that
had been missed in the screening process before the beginning of
the drug trials and had not resulted from R5 mutation during the
course of drug treatment. Thus, these clinical trials suggest that
maraviroc could be a good possibility for “salvage therapy” for
those HIV+ individuals who have experienced treatment failures in
the current categories of HIV/AIDS medications. More studies are
still needed, however, to determine the long-term effects of
antagonizing the CCR5 receptor.

The CCR5Δ32 genetic mutation and the recent research investigating
it and its therapeutic implications are very relevant topics given
the fact that the HIV/AIDS pandemic is one of the greatest public
health concerns in the world, especially in developing nations. As
cited in Lieberman-Blum et al. (2008), the Joint United Nations
Programme on HIV/AIDS and the World Heath Organization report that
as of 2007 33.2 million people worldwide were HIV+, and 2.5 million
of those cases were new infections. In addition, the virus’s high
mutation rate makes viral resistance to current antiretroviral
medications a growing problem for disease treatment. The research
into the CCR5Δ32 mutation aided scientists in developing the new
class of antiretroviral drugs known as CCR5 antagonists.
Furthermore, most new infections of HIV-1 are caused by R5 (also
known as CCR5-tropic or macrophage-tropic) viral isolates. Thus,
gene therapy involving the complete downregulation of CCR5 by the
CCR5Δ32 mutation inserted into cells via viral vectors could one
day prevent transmission of HIV by removing the coreceptor in the
semen-receiving individual. Through the CCR5Δ32 mutation, evolution
and natural selection may have unwittingly supplied we humans with
a very powerful weapon in the fight against the HIV/AIDS
pandemic.


For more information, please see:

Agrawal, L., Jin, Q., Altenburg, J., Meyer, L., Tubiana, R.,
Theodorou, I., Alkhatib, G. 2007. CCR5Δ32 Protein Expression and
Stability Are Critical for Resistance to Human Immunodeficiency
Virus Type 1 In Vivo. Journal of Virology 81: 8041-8049.

Lieberman-Blum, S.S., Fung, H.B., Bandres, J.C. 2008. Maraviroc: A
CCR5-Receptor Antagonist for the Treatment of HIV-1 Infection.
Clinical Therapeutics 30: 1228-1250.

Nazari, R., Joshi, S. 2008. CCR5 as Target for HIV-1 Gene Therapy.
Current Gene Therapy 8: 264-272.