Page 59 - AIDSBK23C

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trials: a recombinant protein of the HIV-1 envelope (AIDSVAX), a nonreplicating adenovirus
serotype 5 vector expressing an internal HIV-1 protein (gag), and a combination of a canarypox
vector expressing HIV-1 immunogens (ALVAC) and the previously studied recombinant HIV-1
envelope protein (AIDSVAX). This third candidate vaccine had modest efficacy (31.2%) and
short-lived, but there was an efficacy signal.[320]
Blocking HIV entry into host cells is another strategy that holds promise. HIV entry is a
complex process involving several key steps. In addition, HIV infection is typically established
by just a few "founder" viruses. Topical microbicides might prevent HIV virions from reaching
susceptible host cells.[321]
The initial step of HIV attachment via the CD4 receptor could be blocked by soluble
preparations of CD4 to bind viral gp120 and prevent attachment to cellular CD4, or blocking of
the CCR5/CXCR4 co-receptors. This approach could potentially work in the period immediately
following HIV exposure. Trials of a multivalent form of CD4 have been shown to block
transmission of HIV, but weekly infusions would be required to maintain plasma levels adequate
for sustained efficacy.[322] The entry inhibitors in clinical development include vicriviroc and
maraviroc, both selective CCR5 antagonists that prevents membrane fusion by blocking binding
of the viral envelope protein gp120 to CD4 þ T cell co-receptors. It is important to note that this
drug binds to a human target and not an HIV target.[280]
The enzyme HIV-1 integrase catalyzes incorporation of viral DNA into the host’s genomic
material and has been considered an attractive drug target for some time. Raltegravir and
elvitegravir are both integrase strand transfer inhibitors (InSTI), which specifically target the
final of three steps by which viral DNA is inserted in to the cellular genome.[280]
Use of immunologic therapy to boost the body's immune response with an immunogen
has been tried and found unsuccessful. The immunogen was a whole inactivated HIV isolate
stripped of envelope proteins and conjugated with incomplete Freund adjuvant.[323]
Genetic modulation of HIV may be possible. There are mechanisms by which HIV
becomes latent in host cells via multiple restrictions on proviral expression. Several transcription
factors are known to recruit histone deacetylases and other complexes to the HIV-1 long terminal
repeat (LTR) promoter, which results in histone modifications within chromatin at the HIV
promoter that limit the ability of RNA polymerase to initiate transcription. Cellular miRNAs that
bind HIV mRNAs may also restrict translation of early expressed HIV mRNAs and so reduce
Tat production by HIV.[324]
Clearance of HIV from the host has the possibility of cure. Novel methods for clearance
include: (1) human stem cell transplantion from a donor with the Δ32 CCR5 mutation; (2)
infusion of ex vivo transformed CD4 cells with zinc finger nuclease (ZFN)-modification; (3)
reduction of latency via epigenetic modification of Nuc-1, a nucleosome located immediately
downstream of the transcription initiation site that impedes long terminal repeat (LTR) activity;
and (4) preventing reactivation of HIV from latent reservoirs.[325]