Control of the worldwide AIDS epidemic requires an effective vaccine. However, the development of an AIDS vaccine has proven an enormous scientific challenge. Vaccine strategies are effective in preventing infections with viruses such as smallpox, poliovirus, and hepatitis B in blocking AIDS virus transmission in animal models. Investigators therefore have studied the immune responses that contain HIV-1 replication in the setting of natural infection and have began to develop vaccine strategies designed to generate these types of immune responses. In fact accruing data have made a compelling argument that CTL (cyto toxic lymphocyte) populations can expand following an AIDS infection and can control viral replication.
In this article, the recent progress in HIV-1 vaccine development is reviewed. The nonhuman primate models used for assessing HIV-1 vaccine strategies are described. Our current understanding of the roles of the cellular and humoral immunity in the containment of HIV-1 replication are discussed, understanding the contribution of CTL in controlling viral spread. Finally, the recent studies are described, demonstrating that vaccine-elicited CTL populations can expand to limit AIDS virus replication in nonhuman primates. These studies raise the possibility that currently available vaccine technologies may be able to contribute to the control of the HIV-1/AIDS epidemic. Current efforts to develop immunogens for inducing neutralizing antibodies are based upon the presumed mechanism by which neutralization occurs and approaches to preserve or induce specific envelope configurations.
The accumulating evidence over the past several years has confirmed the importance of the cellular immune responses uncontrolled HIV-1 replication in humans and SIV replication in rhesus monkeys. The ability to elicit the potent cellular immune responses has therefore become a priority for HIV-1 vaccines will need to elicit potent cellular immune responses has therefore become priority for the HIV-1 vaccine candidates.
Evidences from studies
The evidences from various studies suggest that the loss of HIV-1 specific CD4+ CTL leading to eventual failure of immune control of viremia and clinical disease progression. It is therefore lively the effective HIV-1 vaccines will need to elicit potent virus-specific CD4+ as well as CD8+ T-cell responses. These discrete steps in entry provide a number of opportunities for antibodies to neutralize HIV-1. However, all attempts to generate neutralizing antibodies have resulted in highly focused antibody responses that target a very narrow range of HIV-1 variants. The atomic structure of the gp120 core helps explain why it is difficult to generate across reactive neutralizing antibodies. Information regarding neutralizing antibody epitopes on primary HIV-1 isolates has been limited to studies done using only three human monoclonal antibodies. Two of these monoclonal antibodies, mIGGIb12&2G12, recognize gp120, the antibodies provide evidence that both Env subunits are more potentially important than immunogens. Despite efforts by many investigators, the elicitation of the antibodies with similar antibodies with similar specificities using experimental immunogens has remained elusive.
Although cellular immune responses play a central role in controlling HIV-1 replication, humoral immune response can also be contributed to the control of the virus. Much of the evidence of this is derived from studies in nonhuman primates. Neutralizing monoclonal antibodies have recently been shown to confer passive protection to rhesus monkeys against the challenge with a highly pathogenic SHIV that expresses the envelope glycoproteins of the primary HIV-1 virus isolates. Moreover, when neutralizing the antibodies was elicited in monkeys immunized with Env glycoproteins, these monkeys were protected against SHIV challenges.
These studies suggest that neutralizing antibodies may be capable of conferring protection against and AIDS virus infection. Inactivated virus vaccines have elicited immunity that prevents infection with polio & influenza. While a report in 1989 described protection of monkeys from SIV challenge using inactivated virus vaccine, subsequent studies raised the possibility that this protection was an experimental artifact. In view of the success full use of recombinant proteins as an immunogen for eliciting protective immunity against hepatitis B virus, considerable effort has been devoted to developing are combinant protein vaccine for HIV-1. The monomeric recombinant envelope glycoprotein gp120 has been evaluated as an immunogen in nonhuman primate AIDS models and in human volunteers.
Thus the traditional strategies for creating vaccines have proven disappointing when applied for the prevention HIV infection. The reasons for the failure of these approaches were not clear. There is no evidence that one can uncouple the replication capacity of a virus and its pathogenecity.
Limitations
Currently available antiretroviral therapies for HIV-1 infected individuals have significant limitations. These limitations include cost, toxicities, the propensity to select for drug-resistant viral isolates, and the inability of these drugs to eliminate all reservoirs of virus in infected individuals. Insight of accumulating factor of evidence for the importance of cell-mediated immunity, in containing HIV-1 replication and demonstrating development of the novel vaccine strategies for eliciting cell-mediated immunity, some investigators have suggested that the vaccines might be useful for augmenting virus specific immune responses in infected individuals. Therapeutic vaccination and other immunlogic therefore may be the potential to be useful as adjunctive therapies.
Perhaps the most convincing evidence that the functional immunity to HIV-1 can be augmented in infected individuals has come from recent clinical studies involving structured or supervised treatment interventions (STLs). The initiation of treatment in the patients very early in the period of the acute infections preserves HIV-1-specific CD4+ T-cell responses in these individuals. While stopping the therapy in these patient leads to the immediate and dramatic rise in levels of replication virus, the circulating virus stimulated virus–specific immune responses. These immune responses were capable of controlling the virus replication after the first interruption of the therapy in a subset of individuals, and majority of the study subjects effectively controlled viral replication after subsequent STLs.
These beneficial therapeutic effects of STLs however have only been achieved in small-scale fraction of the patients treated very early in the period of acute infection. Treatment discontinuation or STLs in patients in whom antiretroviral drugs were initiated later during the course of infection have been significantly less successful.
It has been evident for many years to investigators assessing HIV-1 vaccine strategies in nonhuman primate models that vaccinated animals not protected from the infection with a pathogenic immunodeficiency virus frequently survived for a prolonged period of time following viral challenge. It was, however, difficult to document this observation definitively until recently. A number of recent advances have facilitated a precise evaluation of this phenomenon. First technologies have been developed that allow the precise quantitation of plasma viral load as well as vaccine elicited CTL in monkeys. The use of these technologies has allowed the assessment of correlations between the vaccine elicited immune responses and both the virologic and clinical outcomes following immunodeficiency virus infections. Second, a correlation was conclusively demonstrated between the viral load and rate of disease progression in previously unvaccinated SIV/SHIV-infected monkeys. These enabled investigators to hypothesize that set-point viral load may serve as primary endpoint in vaccine challenge studies.
Recent advances in our understanding of the immunopathogenesis of HIV-1 infection are currently being harnessed in the development of a new generation of candidate AIDS vaccines. A number of vaccine strategies that elicit potent virus specific cellular immune responses have already been developed. Immune responses elicited by these vaccines control viral replication and prevent clinical AIDS in rhesus monkeys following pathogenic viral challenges. These studies suggest that currently available vaccines technologies may be capable of eliciting immune responses that can show clinical disease progression and reduce transmission rates by reducing viral loads even if they fail to provide sterilizing immunity in human populations. However, these findings in monkey models may not accurate to predict utility in humans. Human trials evaluating the safety, immunogenicity, and efficacy of these promising vaccine candidates are now being pursued.
(The authors are with Birla Institute of Technology & Science, Pilani).
Rajasthan–333 031. anantha@bits-pilani.ac.in