There are two different types of adaptive immune responses against virus. The word "adaptive" is used to counter against the word "innate". Adaptive immune responses involve cell mediated immune responses and antibody mediated immune responses. Cell mediated immune responses are delivered by T cell, while antibody-mediated immune response, also called humoral immune response, by antibody produced by B cells.
It is generally regarded that viral infection is cleared by both cell mediated and antibody mediated immune responses. Cell mediated immunity (CMI) involves killing virus infected cells by cytotoxic T cells (CTL, or CD8 T cells) that are specific to a virus derived peptide presented by an MHC class I molecule. Since virus-peptide specific cytotoxic T cells are very rare, it takes several days to weeks to generate enough CTLs to fight against virus specific T cells. However, once enough CTLs were generated and fight off the virus-infected cells, the majority of them dies and a small number of cells are saved for the future use. Those saved are called memory CTL. They are quick to respond to the second encounter of the same virus infected cells and that is the basis for the T cell vaccine against a specific virus.
Antibody mediated immune (AMI) response is delivered by antibodies that were generated against the cell surface (exposed) antigen. To induce AMI by vaccination, it is critical to generate a specific cell surface molecule (called epitope) that is ready to elicit antibody against it. Soluble antibody is generated by mature B cells (or plasma cells; secreted antibody producing cells). Once generated, antibody recognizes certain part of the virus and antibody coated virus becomes readily taken care of by several mechanisms, including the opsonization. Unlike cell mediated immune responses, antibody directly recognizes virus outside of the cells.
In most cases, it is either CMI or AMI protects hosts against a variety of infections of pathogenic viruses. However, innate immune responses always try to take care of them in the first place. It is not clear which one of the two adaptive immune responses, or both, were actually involved in protections against a specific viral infection. It is not apparent whether our immune system chose one or another if they failed to take care of a pathogen in the first place. Who will decide which one of the two adaptive immune system, CMI or AMI, to use?
CD4 T cells are essential components for CMI and AMI in several various steps. It requires several books to cover the detailed information on the role of CD4 T cells in immunity .
Scientists have been struggling for the last two to three decades to generate a vaccine against HIV without any noticeable progress. Initially, it was against cell surface molecules, env, to generate antibodies against it. It did not work out. I am not so sure what were the criteria for evaluating vaccine efficacy. They switched back to a vaccine strategy which is geared towards generating CTLs against intracellular proteins, gag, pol and nef. Big scale trials, called STEP, resulted in an increase in HIV infection in vaccinated individuals. It was haulted prematurely for an apparent reason, increase in HIV susceptibility after immunization. Recent story, called RV144, evolves around antibody mediated immune responses, even though it is still under investigation. It showed positive data for the first time. 51 people out of 8000 vaccinated were infected with HIV, while 74 were infected with HIV among the similar number of unvaccinated control group. They claimed that it is very significant statistically, 30% of vaccine efficiency, even though it seems not a thrilling number. Currently, active study is ongoing to understand what made RV144 was marginally successful, especially to understand which immune correlates are different between uninfected and infected individuals among participants of RV144. The progress has been published recently in Nature Immunology (NATURE IMMUNOLOGY VOLUME 13 NUMBER 5 MAY 2012).
http://www.nature.com/ni/journal/v13/n5/full/ni.2264.html
I will summarize the RV144, in a separate article.
Recent meeting "CROI 2012" has a very intense discussion on RV144. Dr. Richard Koup of VRC summarized the current status on HIV vaccine in his presentation with a sum of RV144.
http://retroconference.org/static/webcasts/2012/
Issues needed further consideration:
It is generally regarded that viral infection is cleared by both cell mediated and antibody mediated immune responses. Cell mediated immunity (CMI) involves killing virus infected cells by cytotoxic T cells (CTL, or CD8 T cells) that are specific to a virus derived peptide presented by an MHC class I molecule. Since virus-peptide specific cytotoxic T cells are very rare, it takes several days to weeks to generate enough CTLs to fight against virus specific T cells. However, once enough CTLs were generated and fight off the virus-infected cells, the majority of them dies and a small number of cells are saved for the future use. Those saved are called memory CTL. They are quick to respond to the second encounter of the same virus infected cells and that is the basis for the T cell vaccine against a specific virus.
Antibody mediated immune (AMI) response is delivered by antibodies that were generated against the cell surface (exposed) antigen. To induce AMI by vaccination, it is critical to generate a specific cell surface molecule (called epitope) that is ready to elicit antibody against it. Soluble antibody is generated by mature B cells (or plasma cells; secreted antibody producing cells). Once generated, antibody recognizes certain part of the virus and antibody coated virus becomes readily taken care of by several mechanisms, including the opsonization. Unlike cell mediated immune responses, antibody directly recognizes virus outside of the cells.
In most cases, it is either CMI or AMI protects hosts against a variety of infections of pathogenic viruses. However, innate immune responses always try to take care of them in the first place. It is not clear which one of the two adaptive immune responses, or both, were actually involved in protections against a specific viral infection. It is not apparent whether our immune system chose one or another if they failed to take care of a pathogen in the first place. Who will decide which one of the two adaptive immune system, CMI or AMI, to use?
CD4 T cells are essential components for CMI and AMI in several various steps. It requires several books to cover the detailed information on the role of CD4 T cells in immunity .
Scientists have been struggling for the last two to three decades to generate a vaccine against HIV without any noticeable progress. Initially, it was against cell surface molecules, env, to generate antibodies against it. It did not work out. I am not so sure what were the criteria for evaluating vaccine efficacy. They switched back to a vaccine strategy which is geared towards generating CTLs against intracellular proteins, gag, pol and nef. Big scale trials, called STEP, resulted in an increase in HIV infection in vaccinated individuals. It was haulted prematurely for an apparent reason, increase in HIV susceptibility after immunization. Recent story, called RV144, evolves around antibody mediated immune responses, even though it is still under investigation. It showed positive data for the first time. 51 people out of 8000 vaccinated were infected with HIV, while 74 were infected with HIV among the similar number of unvaccinated control group. They claimed that it is very significant statistically, 30% of vaccine efficiency, even though it seems not a thrilling number. Currently, active study is ongoing to understand what made RV144 was marginally successful, especially to understand which immune correlates are different between uninfected and infected individuals among participants of RV144. The progress has been published recently in Nature Immunology (NATURE IMMUNOLOGY VOLUME 13 NUMBER 5 MAY 2012).
http://www.nature.com/ni/journal/v13/n5/full/ni.2264.html
I will summarize the RV144, in a separate article.
Recent meeting "CROI 2012" has a very intense discussion on RV144. Dr. Richard Koup of VRC summarized the current status on HIV vaccine in his presentation with a sum of RV144.
http://retroconference.org/static/webcasts/2012/
Issues needed further consideration:
- It seems that the pendulum for the HIV vaccine is leaning towards the generating broad neutralizing antibodies (BnAb) at the moment.
- High affinity antibodies will require a lot of help from the follicular helper T cells (TFH), in several steps of their development.
- It will be interesting to see whether neutralizing antibody against HIV (SIV) is present (abundant) in lucky individuals with homozygous mutant CCR5 gene (CCR5delta32) or not.
- It will be interesting to see whether BnAB is generated from non-pathogenic infection of SIV into non-human primates.
- If they do have high titer of anti-HIV (SIV) antibodies, it suggests that the lack of neutralizing antibodies are not necessarily due to an innate difficulty of generating antibody against HIV, but the lack of functional HST causes the inability to generate neutralizing antibodies against HV.
- It will suggest that the loss of HST is directly involved in the generation of BnAb.
- There is a strong possibility that TFH cells could be missing in HIV infected individuals, due to the lack of HST.
- It will suggest that our current paradigm that TFH is derived from naive T cells will require further examination.
- It is also applied to the generation of Th17 cells, which is lacking in HIV infected individuals with many naive T cells.
Key words:
AIDS, HIV, vaccine, HST, Adaptive Immune responses, innate immune responses, B cell, T cells, humoral immunity, cell mediated immunity (CMI), antibody mediated immunity (AMI), Humoral immune response, STEP, RV144, CCR5, CCR5delta32, env, gag, pol, nef, CTL (cytotoxic T cell), CD8 T cell, TFH, Th17, naive T cell, CROI, Richard Koup, VRC (Vaccine research center)
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