The human immune system uses both innate and adaptive immune responses to combat pathogens such as viruses and bacteria (see VAX March 2004 Primer on Understanding the Immune System, Part II). Innate immune responses are always on standby and can act quickly, usually within hours, to either snuff out or help limit an initial infection. If more help is needed, adaptive immune responses?which include both antibodies and cellular immune responses?kick in. These take longer to activate because they are designed to target a specific pathogen. The immune system generates HIV-specific antibodies and cellular immune responses against the virus, both of which are critical in either preventing or controlling the infection, and are therefore of great interest to AIDS vaccine researchers.
Antibody responses are Y-shaped molecules that primarily latch on to viruses and prevent them from infecting cells (see VAX February 2007 Primer on Understanding Neutralizing Antibodies). Once cells are already infected, cellular immune responses come into play. These responses involve a subset of immune cells known as CD4+ T helper cells that orchestrate the activities of activated CD8+ T cells, known as cytotoxic T lymphocytes (CTLs), which can kill cells already infected by the virus.
The role of cellular immune responses in HIV infection is complicated because the very cells that play a role in limiting infection are under attack?the virus preferentially targets and infects CD4+ T cells, severely hampering the immune system's ability to fight back. However, both CD4+ and CD8+ T cells still play a critical role in the control of HIV infection and are also likely to be important to the development of an AIDS vaccine. Researchers are now studying the ideal types of antibodies and cellular immune responses that a vaccine should induce to best prevent or control HIV infection.
Inducing T-cell responses
Developing AIDS vaccine candidates that are capable of inducing neutralizing antibody responses against HIV is challenging and so far the strategies tested have been unsuccessful. However, several AIDS vaccine candidates have been identified that can induce cellular immune responses, both CD4+ and CD8+ T cells, against HIV. Many of these have been evaluated in clinical trials, including Merck's MRKAd5 vaccine candidate that was recently tested in the STEP trial (see VAX September 2007 Special Report).
Typically, researchers measure the size of the cellular immune responses that are induced by different candidates, as well as the ability of these cells to secrete cytokines, which are proteins produced by immune cells in response to viruses or bacteria (see VAX August 2007 Primer on Understanding Immunogenicity). Merck's MRKAd5 candidate induced T cells secreting a cytokine known as interferon-γ (IFN-γ) in more individuals than any candidate tested in Phase I clinical trials, prior to it being advanced to a Phase IIb test-of-concept trial. In Phase I trials, 80% of MRKAd5 recipients, who did not have high levels of pre-existing immunity to the cold virus used as a vector, developed T cells that secreted IFN-γ.
The majority of vaccine recipients in the STEP trial also developed both CD4+ and CD8+ T-cell responses against HIV after receiving MRKAd5. But these immune responses were not sufficient to protect against infection. Researchers have not observed any correlation so far between the size of HIV-specific immune responses in vaccine recipients and whether or not they subsequently became infected with HIV through risk behaviors, such as unprotected sex with an HIV-infected partner or injection-drug use.
Researchers have also found that the quantity of T-cell responses does not seem to correlate with control of the virus in some HIV-infected individuals, known as elite controllers, either. Elite controllers are a group of long-term nonprogressors who are HIV infected yet have very low levels of virus (viral loads) and do not progress to AIDS, even without the aid of antiretroviral therapy (see VAX September 2006 Primer on Understanding Long-term Nonprogressors). The magnitude of HIV-specific cellular immune responses are actually lower in elite controllers than those seen in individuals with typical viral loads who have normal disease progression.
Quantity vs. quality
Together these findings indicate that the size of the T-cell response may not be the key factor in either preventing or controlling HIV infection. Instead, the capability of the T cells to perform a particular function may be more important. Some immunologists suggest that it is not the size of the initial T-cell response to vaccination that matters, but the ability of these T cells to multiply later on, when the individual encounters the pathogen they were vaccinated against, that is most critical.
Other researchers are studying the direct ability of the T cells induced by an AIDS vaccine candidate to kill virus-infected cells. Researchers can extract T cells from volunteers in an AIDS vaccine clinical trial through blood samples and test them in a laboratory against HIV to see if they are actually capable of killing virus-infected cells. This method is now being used by some researchers to prioritize vaccine candidates in Phase I clinical trials.
Another approach is to study different viral and bacterial vectors that may be used for AIDS vaccine candidates to see if they induce different types of T-cell responses. Researchers have conducted preclinical experiments in mice to compare the T cells induced by different viral vectors. The results indicate that the choice of vector does affect the type of T cells that are induced upon vaccination.
Researchers are also currently studying the characteristics of effective T-cell responses in other viral infections, in which cellular immune responses are at least partly responsible for protection, to determine what types of T cells an AIDS vaccine candidate should ideally induce. More research on T-cell responses to HIV, as well as other pathogens, will shed light on these questions and help researchers design more effective AIDS vaccine candidates.