Since the beginning of the epidemic, 85.6 million [65.0–113.

0 million] people have been

infected with the HIV virus and about 40.4 million [32.9–51.3 million] people have died of
HIV. Globally, 39.0 million [33.1–45.7 million] people were living with HIV at the end of
2022.

An estimated 0.7% [0.6-0.8%] of adults aged 15–49 years worldwide are living with HIV,
although the burden of the epidemic continues to vary considerably between countries and
regions. The highest prevalence of HIV occurs in parts of Asia and sub-Saharan Africa.

More than 40 million people, mostly women and children, are presently infected by the
human immunodeficiency virus (HIV); almost all horizontal and vertical transmissions of
HIV infection are due to HIV strains that use the CCR5 coreceptor expressed on mucosal
surface.

The C-C chemokine receptor type 5 (CCR5) is a key player in HIV infection due to its major
involvement in the infection process.
It is involved in virus entry and cell-to-cell spread: Such R5-tropic viruses are nearly always
involved in the initial infection, while HIV strains using the CXCR4 coreceptor are observed
only seldomly in the early infection.
It mainly belongs to a large family of chemokine receptors that are expressed on surface of
lymphocytes and other cell types, where they are involved in signaling and coordination of
immune responses.

Due to the natural history of HIV infection, CCR5 is a key target for the development of
drugs and immunogens that are able to elicit systemic and especially mucosal responses to
protect exposed people from infection.
However, a genetic mutation known as CCR5-delta 32 is responsible for the two types of
HIV resistance that exist. CCR5-delta 32 hampers HIV's ability to infiltrate immune
cells. The mutation causes the CCR5 co-receptor on the outside of cells to develop smaller
than usual and no longer sit outside of the cell. CCR5 co-receptor is like door that allows HIV
entrance into the cell. The CCR5-delta 32 mutation in a sense locks "the door" which
prevents HIV from entering into the cell. 1% of people descended from Northern Europeans,
particularly Swedes, are immune to HIV infection. These lucky people are homozygous
carriers of the mutated gene - meaning that they inherited a copy from both of their parents.
Another 10 -15% (the number has even suggested to be 18%) of people with European
heritage inherited one copy of the gene. Just one copy of the mutation does not prevent
against infection. It does however reduce carrier's chances of infection and delays the
progress of AIDS. Since the CCR5-delta 32 is tied primarily to the Eurasia region, the
mutation has not been found in Africans, East Asians, or Amerindians.

Structure and role of CCR5 for viral infection and internalization:

CC chemokine receptor 5 (CCR5) is expressed on surfaces of immune cells. It is comprised

of 7 transmembrane (TM) domains, 3 extracellular loops and 4 intracellular loops, an
extracellular N-terminal domain, and an intracellular C-terminal domain.
 The TM domains are thought to be arranged in a cluster, similar to the resolved crystal
structure of another 7 TM G protein–coupled receptor, rhodopsin.

The amino terminus (NH2) extracellular domain and the clustered first and second
extracellular loops are important in binding chemokine ligands to the receptor. When an
agonistic chemokine ligand binds to CCR5, the receptor is thought to undergo
a conformational change. This activates G protein bound to intracytoplasmic domains of the
receptor. G protein dissociates and activates phospholipase C that generates the second
messengers inositol-1,4,5- triphosphate and diacylglycerol. These events lead to release of
intracellular calcium and activation of protein kinase C.
Chemokine binding to CCR5 may also trigger other intracellular activation pathways
independent of G protein activation, including those mediated by mitogen activated protein
kinases.
Phosphorylation of serines in the intracytoplasmic C terminal portion of the receptor by
protein kinase C and G protein–coupled receptor kinases triggers recruitment of β-arrestins.
β-arrestins are multifunctional proteins that help mediate G protein–independent signaling
and help link CCR5 to clathrin to initiate receptor endocytosis. Caveolae-dependent
mechanisms also may contribute to receptor endocytosis. Within the endosome, the receptor
is dephosphorylated and is recycled back to the cell surface.

Treatment targeting CCR5 receptor:

With the appreciation that CCR5 is necessary for HIV cellular entry and that CCR5 is the key
coreceptor for most HIV strains in infected persons, several strategies that target this element
are in development for prophylaxis and treatment.

I. CCR5 Agonists: chemokine binding to CCR5 is an agonistic event that results in

intracellular signal transduction and internalization of the coreceptor. A number of amino
terminus–modified chemokine analogues have been developed that are substantially more
active HIV inhibitors than the native RANTES.

II. CCR5 Antagonists: There are 2 classes of CCR5 antagonists in development

 Monoclonal antibody to CCR5: The humanized monoclonal antibody HGS Ab004
(Human Genome Sciences, Rockville, Md) binds to the second extracellular loop of
CCR5, thereby inhibiting both chemokine and HIV envelope binding.

 Small molecule antagonists: they are likely to be an allosteric inhibitor that locks
CCR5 into a conformation such that it is not able to bind HIV envelope protein. Each
can function as a receptor antagonist, blocking to various degrees the signals induced by
different receptor-binding chemokines. By blocking CCR5 activity, they may block the
cellular trafficking and activation that is mediated by CCR5.

III. Nonagonistic Nonantagonistic CCR5 Inhibitors: Pro-140 is a humanized monoclonal

anti- CCR5 antibody that inhibits HIV entry by binding to the second extracellular loop of
CCR5 but neither signals nor blocks the function of the receptor at concentrations
sufficient to block HIV entry.