In
an effort to prevent sexual transmission of HIV, researchers are studying various
microbicides, substances that can be inserted into the vagina
(and, potentially, the rectum) to prevent infection.
Two
recently published studies shed further light on development of topical microbicides.
Entry
Inhibitors
In
the first study, researchers assessed the activity of various entry inhibitors
against HIV-1 isolates in vitro:
BMS-378806 (which targets HIV-1
gp120);
BMS-C (a BMS-378806 derivative);
CMPD167 (a CCR5 co-receptor inhibitor);
AMD3465 (a CXCR4 co-receptor inhibitor);
C52L (a peptide fusion inhibitor).
Some
of these agents have been shown to block vaginal infection in monkeys. However,
the authors noted, an effective microbicide must be
active against multiple HIV-1 variants. Therefore, they tested the agents alone
or in combination against 25 primary
R5-tropic, 12 X4-tropic, and 7 R5X4-tropic isolates of HIV-1 subtypes A-G.
They
found that at high concentrations (0.1-1 muM), CMPD167
inhibited replication of most R5-tropic isolates in human donor lymphocytes by
more than 90%. At lower concentrations, double and triple combinations were more effective than individual inhibitors.
Similar results were obtained with AMD3465 against X4-tropic viruses. Dual-tropic
R5X4 virus strains were inhibited by combining CMPD167 and AMD3465, or by using the coreceptor-independent compounds.
The
authors thus concluded that, “combining
entry inhibitors may improve microbicide effectiveness.”
Safety
Markers
Microbicide
development has been hampered by the absence of surrogate safety markers. The
objective of the second study was to develop a murine
(mouse) model to examine the mucosal response to microbicides
and to assess the functional implication of observed changes.
Mice
received 14 daily intravaginal doses of nonoxynol-9
(which has been shown to cause vaginal and rectal inflammation in humans), PRO
2000, or a placebo gel. As expected, nonoxynol-9 induced an inflammatory response
characterized by increased levels of cytokines and chemokines,
recruitment of neutrophils and monocytes
into the genital tract, and activation of the transcription factors NF- kappa B and activator
protein-1. However, minimal inflammation was observed in response to a 2% PRO
2000 formulation.
In
addition, mice treated with nonoxynol-9 were significantly more susceptible to
challenge with a low dose of herpes simplex virus type 2. But mice treated with
PRO 2000 had a similar response to those treated with placebo.
These
findings suggest that PRO 2000 has little deleterious effect on mucosal immunity,
and support the use of this mouse model in preclinical evaluation of future microbicide
candidates.
05/15/07
References
TJ
Ketas, SM Schader, J Zurita, and others. Entry inhibitor-based microbicides
are active in vitro against HIV-1 isolates from multiple genetic subtypes. Virology. April 9, 2007 [Epub
ahead of print].
BT Galen, AP Martin, E Hazrati, and others. A comprehensive murine model
to evaluate topical vaginal microbicides: mucosal inflammation
and susceptibility to genital herpes as surrogate markers of safety. Journal
of Infectious Diseases 195(9): 1332-1339. May 1, 2007.
Index
of All HIV and AIDS Articles by Topic ( A to Z)
