SP-10:
AN ADJUVANT TREATMENT FOR HIV
The long-term use of antiretroviral therapy in the
treatment of HIV is sometimes hampered by poor compliance
due to pill burden, food restrictions, and major side
effects that impact Quality of Life. Furthermore,
one of the major reasons for therapy failure is the
emergence of resistant virus against one or more of
the anti-HIV medications or, to some extent, an entire
class of drug (cross resistance). The rapid rate of
mutation of HIV-1 and conferred resistance of the
virus to current therapies continues to necessitate
a need to develop improved new therapeutic agents.
SP-10 is an anti-retroviral therapeutic that has demonstrated
promise in preclinical studies due to its efficacy,
favorable safety profile, and promising resistance
profile. SP-10 inhibited the replication of CCR5-
and CXCR4-sensitive HIV-1 viral strains in vitro in
engineered HeLa cells expressing CD4, CXCR4 and CCR5
and in peripheral blood monuclear cells. When the
host cells where pre-incubated with SP-10 prior to
viral infection, SP-10 efficacy was comparable to
the classic antiviral agent AZT.
Pre-incubation
of MAGI-HeLa cells with SP-10 resulted in a decrease
of CD4 and CCR5 receptors expression at the cell surface
but did not modify the total CD4/CCR5 protein amount
present in the cell. As a consequence, gp120 binding
on the cell membrane was significantly inhibited.
The reduction of the density of these specific receptors
at the cell surface was associated to an alteration
of the actin accumulation and a reduction of F-actin
filaments formation near the cell surface suggesting
that SP-10 interference with the actin polymerization/depolymerization
dynamic was a key element in the reduction of CD4
and CCR5 cell surface density.
In
addition, SP-10 also decreased cholesterol uptake
and also the expression of the cholesterol synthesis
key enzyme HMG-CoA reductase mRNA in the cells. This
effect is purported to induce a modification of the
host cell lipid enriched raft composition and membrane
fluidity which in turn would lead to an alteration
of recruitment of the receptors used by HIV to enter
the cell.
The
fact that SP-10 aims at several targets that are specific
of the host cell and not of the virus itself supports
the idea that it will be very difficult for the virus
to develop resistance. The inhibition of the multi-drug
resistant HIV-1 MDR769 replication by SP-10 further
supports this claim.
In addition SP-10 demonstrated a very low toxicity
profile in vitro.
