The Joint United Nations Program on HIV-1/
AIDS (UNAIDS) announced its goal to stop HIV-1 transmission by
antiviral (
HAART) treatment of patients since at the end of 2003 the number of people living with HIV-1 was 38 million, 25 million in the sub-Saharan region of Africa. The present review deals with a new approach to simultaneously treat HIV-1/
AIDS patients in HIV-1 endemic regions with CpG
oligodeoxynucleotides (ODNs) and people at high risk of
infection with a
vaccine containing CpG ODNs combined with synthetic HIV-1
peptides by intranasal and intradermal applications. During HIV-1
infection a gradual increase in the levels of
IL-4 and
IgE in the patients' serum, was reported. It was suggested that such an increase of the
cytokine IL-4 and the
IgE immunoglobulin are interconnected and may serve as indicators for the coming stage of
AIDS. It was also suggested that the
IL-4 and
IgE increase in the serum of HIV-1 infected people resemble the increase of
IL-4 and
IgE levels in allergic patients that were exposed to endogenous or environmental
allergens [Becker, Virus Genes 28, 5--18, 2004]. Indeed, it was reported that the HIV-1 virions' shed gp120 molecules, which contain a
superantigen (superallergen) domain that enables the viral
glycoprotein to bind the V(H)3 domain of
IgE molecules that are bound to FcepsilonRI+ hematopoietic cells [basophils, mast cells, dendritic cells (DCs) and plasmacytoid DCs (pDCs)]. Such interaction was reported to induce the hematopoietic cells to release large amounts of Th2
cytokines IL-4,
IL-5,
IL-10 and
IL-13. These findings led to the hypothesis [Op.
cit.] that the cure of HIV-1/
AIDS patients requires the induction of endogenous synthesis of
type I interferons (INF alpha and beta) with a bacterial CpG rich
DNA that will induce the patients' pDCs to release large amounts of type I IFNs. Under these conditions HIV-1 replication in polarized to Th2 cells is inhibited. Type I IFNs reactivate the patients' inhibited Th1 cells to synthesize
IL-2 and
IL-12 cytokines that activate the maturation of CTL precursors. The unmethylated
bacterial DNA activates B synthesis to switch to
IgG and
IgA synthesis. The novel
drug CpG ODNs is being tested for the prevention and the treatment of allergic humans and in the experimental system of allergic mice. It was also reported that treatment of mice with
CpG ODN prior to or after
retrovirus infections protected and cured, respectively, the
retrovirus infection. It was also reported that CpG ODNs treatments of mice exposed to
allergen protected them against the development of the allergic response. Phase I treatment of healthy people with CpG ODNs provided information on the safety of these compounds. The CpG ODNs A and B bind to
Toll like receptors that are present in pDCs and B cells, respectively,
CpG ODN - A is the
ligand for TLR9+ pDCs and induce the release of large amounts of IFN-alpha, beta.
CpG ODN-B is the
ligand for TLR9+ in B cells and induce the synthesis of
IgG and
IgA.
CpG ODN-C contains motifs from CpG ODNs A and B and is more active. The present review is based on findings from studies that reported that CpG ODNs treatment of retrovirus infected mice, monkeys and allergic mice prevented the virus and
allergens caused diseases, respectively. Based on these studies, a hypothesis is presented that treatment of HIV-1 infected and
AIDS patients with
CpG ODN-A and B or
CpG ODN-C have the potential to inhibit
IL-4 synthesis and release from FcrepsilonRI+ hematopoietic cells by inducing TLR9+ pDCs to release large amounts of type I IFNs. TLR9+ B cells are induced by
CpG ODN-B to switch from
IgE to
IgG,
IgA synthesis. In addition, type I IFNs (alpha, beta) have the capacity to inhibit HIV-1 replication in polarized Th2 cells. Type I IFNs reactivate the patients' Th1 cells to synthesize
IL-2 and
IL-12 cytokines, activators of the precursor cytotoxic T cells (CTLs), leading to the reactivation of the inhibited adaptive immune response.
Antiviral CTLs have the ability to clear the
virus infection. The present novel approach to the treatment and of HIV-1/
AIDS patients with CpG ODNs may prevent HIV-1 transmission and the
AIDS pandemic if controlled studies on the treatments with CpG ODNs of HIV-1 infected people will be done by international and private agencies and companies to define the effective treatment regime and the efficacy of the treatments to HIV-1 infected people at different times post-
infection. It is also hypothesized that in order to stop HIV-1 transmission in HIV-1 endemic regions the people at high risk of HIV-1
infection should be treated at the same time as HIV-1 infected people with a
vaccine containing synthetic CpG-ODNs combined with synthetic HIV-1
peptides, compatible with the major HLA haplotypes of the regional population. The
vaccine may be self-applied by people at high risk of
infection by the intra-nasal route and by intra-dermal application as a "peplotion
vaccine". The stimulation of the
antiviral CTL response by HIV-1 infected people and the active
antiviral immune response in the vaccinated population may lead to a decline in HIV-1 transmission and may be a model for control of the HIV-1/
AIDS pandemic.