Page 58 - AIDSBK23C

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NOVEL STRATEGIES FOR AIDS PREVENTION AND TREATMENT

Given the success of mother-to-child prevention of HIV transmission, studies have been
aimed at prevention of HIV infection through other routes of transmission. Transmission of HIV
through sexual intercourse could be prevented if the host immune response in mucosal tissues
could limit the size of the founder population of infected cells below the level required for
establishment of infection. If concentrations of antiretroviral drugs were present that inhibited
viral replication, then infection could not occur. This strategy employs pre-exposure prophylaxis
using available oral antiretroviral drugs. The drugs utilized are those that reach a high
concentration in vaginal and rectal tissues, including emcitrabine (FTC) and tenofovir
(TDF).[313] One study showed a 44% reduction in transmission, but was likely not higher due
to problems with adherence to once daily drug use.[314]
A large component of AIDS research has been aimed at development of an effective
vaccine. Though a universally efficacious vaccine would help stop the spread of AIDS, such a
vaccine would be of little help to the millions of currently HIV-infected persons worldwide.
Vaccine development has encountered several obstacles: HIV epitope variability, HIV
avoidance of immune response through cell to cell transmission, lack of an effective neutralizing
antibody response, and induction of adverse immune reactions through HIV homology to
endogenous human proteins. Several vaccine strategies have been proposed, including induction
of cell mediated and/or humoral immunity.[315]
The most advanced vaccine research centered on the use of the HIV gp120 or gp160
envelope proteins to induce a humoral response. Most neutralizing antibodies formed in persons
infected with HIV are aimed at gp160. However, most research studies have focused on use of
gp120 because it was simpler to manufacture and did not have any major disadvantages
compared to gp160. The immunogenic response may be enhanced by removal of carbohydrate
moieties from the heavily glycosylated gp120.[316] Enhancement of the immune response has
been achieved in trials using lipopeptides, which are hybrid molecules composed of large
synthetic peptide fragments of viral proteins covalently linked to a palmitoyl chain. This lipid
moiety facilitates peptide entry into antigen-presenting dendritic cells to enhance the cell-
mediated immune response.[317]
Alternative approaches include the use of poxviruses such as vaccinia as recombinant
vectors for vaccination with HIV envelope proteins, and this has the advantage of inducing
mucosal immunity that could block infection through the portal of entry in mucosal surfaces.
Development of an attenuated virus vaccine has the potential for induction of the most effective
and long-lasting immunity, but the long latency of HIV infection makes assessment of non-
pathogenicity of such a vaccine difficult to ascertain. Also, the vaccine must be effective against
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the various subtypes of HIV that have arisen or will arise. Through the early 21 century, no
effective HIV vaccine was produced.[35,315,318]
Another approach to control of HIV infection is the use of gene therapy. One approach is
immunization by direct injection of plasmid DNA encoding genes for specific HIV protein
antigens.[315] An approach based upon introduction into susceptible cells, such as CD4
lymphocytes, of a gene that induces apoptosis in infected cells, has been employed with minimal
therapeutic benefit. Gene therapy could be based upon the expression of antiviral genes in the
target cells for HIV, termed intracellular immunization, but is hampered by the large size of the
target CD4 cell population.[319]
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In the early 21 century, just three candidate HIV vaccines completed clinical efficacy