Vaccine against HIV infection is one of the most important laboratory experiences made by research all over the world. But the problem is not solved yet. It is not surprising that there have been many studies of these agents in HIV infection, and much of the knowledge about these substances has come from these groups. In terms of immunoreconstitution, the two most logical candidates are IL-2 and IFN-γ. Both these lymphokines are normally produced by CD4-helper lymphocytes and help to amplify immune responses (Cohen, 2001). In HIV infection the production and regulation of these lymphokines is defective. IFN-γ has several roles. It activates macrophages to kill intracellular pathogens such as mycobacteria, fungi and protozoa, it upregulates MHC class II expression on antigen-presenting cells to stimulate presentation to CD4 cells and generate the necessary lymphocyte proliferation, and it activates NK cells to virucidal and tumoricidal activity.
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All these functions are defective in HIV-infected individuals, but can be improved by adding IFN-γ in vitro and in vivo. Initial clinical trials showed some encouraging effects with immunomodulation in vivo as well as a reduction in HIV antigenemia . It is of interest that as with many cytokines there is a therapeutic window for IFN-γ, and that pushing the dose too high can lead to opposite effects, with a resulting increase in immunosuppression. Placebo-controlled trials are underway to determine whether IFN-γ will give protection from opportunist infections (Eisele, 2008). The role of IL-2 is to activate lymphocytes, in particular cytotoxic T-cell 'killer' cells. It has shown some activity in cancer treatment, when lymphocytes are removed from the patient (the population containing within it tumor-specific cytotoxic cells) and expanded with IL-2 in vitro (Cohen, 2001). These lymphokine-activated killer 'LAK' cells are then injected back into the patient, and target the tumor. The lack of IL-2 production was thought to underlie the susceptibility to viral infections and tumors in AIDS patients, and therefore trials were constructed to test the efficacy of this agent in reconstitution of the immune response. Initial reports did not indicate efficacy and there was concern that IL-2 would activate lymphocytes and thereby enhance HIV replication (Brownlee, 2006).
The road leading to the development of a successful vaccine against HIV contains many obstacles. One major problem has been the lack of an animal model; HIV does not replicate to high titer in chimpanzees, neither do they contract disease. The simian immunodeficiency virus (SIV) of primates, while causing infection, does not mimic HIV infection although some preliminary data suggest that the macaque may be susceptible to HIV-1 (Eisele, 2008). The great variability of the envelope protein of HIV poses yet another problem: there is no guarantee that a vaccine raised against one HIV-1 isolate would be effective against another isolate of HIV-1. The cost of a successful vaccine would also be important. As most HIV infection worldwide is to be found in developing countries, the vaccine would have to be inexpensive and a minimum number of immunizations necessary (Cohen, 2001).
Researchers admit that several strategies are currently being explored. By far the greater number of experiments have been performed using killed whole virus, modeled on the Salk poliomyelitis vaccine. The virus is inactivated with a number of different agents including formalin, Tween-ether (Tween is a non-ionic detergent), β-propriolactone and UV light. Active immunization is greatly facilitated when the inoculation is presented in association with an adjuvant. Various formulations have been tested, for example, muramyl dipeptides, incomplete Freund's adjuvant, immune stimulating complex, and alum (which is the only one of these agents currently licensed for human use). Killed SIV, either from native isolates or molecularly cloned preparations, injected into macaques gives some protection against low doses of the same strain but the best results were obtained if the challenge was not given until 12 months after the final immunization. Other studies demonstrate that killed virus affords protection against intravenously injected virus but not to virus delivered to mucosal surfaces. This will require further investigation. The use of conventionally attenuated live SIV does not prevent infection against a virulent strain but does prevent disease. More encouraging results were obtained when rhesus monkeys were immunized with a live SIV clone containing a nef deletion (Esparza, 2000). These animals were challenged with a pathogenic SIV strain 2 years after the final inoculation and have remained healthy since that time, with normal CD4 counts, for more than 4 years. It is unlikely that a vaccine based on a live attenuated version of HIV-1 would be approved for use in humans until all methods employing non-infectious agents have been exhausted (Cohen, 2001).
Experiments with purified HIV envelope glycoprotein, expressed in a baculovirus or Chinese hamster ovary cell line and having near normal glycosylation, have shown limited success. Although it proved to be safe as an immunogen, antibody titers to gp160, following multiple immunizations in seronegative individuals, were low and diminished rapidly over a 2-year follow-up period. Vaccinia virus has been used as a vector, where gp160 is produced in host cells in association with vaccinia virus infection. This has proceeded as far as a phase 1 clinical trial, inducing both cellular and humoral immunity, and has a more vigorous effect in individuals who had not been previously exposed to vaccinia, for instance, through smallpox immunization (Esparza, 2000). Those individuals with prior exposure could not be boosted with a second live vaccinia-gp160 immunization, as the response to the primary challenge was so strong. However, the use of recombinant gp160 as a boosting agent proved more effective against challenge with SIV when the same experiment was repeated in macaques using vaccinia-SIV gp160 as the primary immunizing agent. Using recombinant gp120 as immunogen showed no more promise than gp160. While the immunogen was well tolerated, disappointingly low titers of non-neutralizing antibodies were produced, although the cell-mediated response to gp120 was fairly strong. In experiments where chimpanzees were immunized with human-derived recombinant gp120 and the challenge was with the homologous HIV isolate, protective immunity was obtained if the neutralizing antibodies were directed at the V3 loop of gp120 (Cohen, 2001).
Most current clinical trials employ recombinant subunits of HIV-1 or HIV-2. Most of these recombinant vaccines have failed to elicit protective immunity in the SIV model in contrast to the apparent success of HIV-1 env subunit immunogens in the chimpanzee. The structural, and therefore immunogenic, differences between SIV and HIV envelope glycoproteins may account for these discrepancies (Vastag, 2007b). The core protein p24 has been used in vaccine trials and has provided some encouraging results. Cynomolgus macaques immunized with HIV p24 preparation possess CD4+ T-cells that recognize both pure p24 and whole inactivated HIV-1. Co-infection of cells with vaccinia-HIV p24 or vaccinia-gp160 constructs induces the production of virus-like particles that express gp160 but lack the HIV genome, and have the potential to induce suitable immune responses without the danger of viral infection (Vastag, 2007a).
Unique determinants are to be found within any given Ig molecule. They are found in all isotypes and are known as idiotypes. Specific antibodies to these epitopes are called anti-idiotypes and are thought, in some cases, to contribute to the pathogenic effects of HIV infection. This principle has been used in vaccine trials. Monkeys were immunized with the anti-idiotype antibody described above in order to induce antibodies that would bind to the CD4 binding site on HIV-1 gp120. The antibody so produced neutralized HIV activity in vitro and further clinical trials in humans are ongoing. Diversity of the virus is one of the major problems: there are at present five known main families of HIV-1 and the difference is as great as 30% in the gag and env gene sequences between the families.
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