CpG ODNs treatments of HIV-1 infected patients may cause the decline of transmission in high risk populations - a review, hypothesis and implications.

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.