Current HIV vaccine trials are based on an assumption that immunization with HIV-derived antigen will result in immunological memory responses, whether they are cell mediated or antibody mediated. Many HIV vaccine trials are unique in terms of choice of HIV-derived antigen used and (or) choice of viral vectors that deliver antigens. Some trials apply the pre-immunization with a piece of DNA derived from HIV genes or some uses whole killed HIV. However, they are essentially all similar in a big picture of our current understanding of immunology. They only differ antigens delivered or vehicles to deliver antigens, hoping that different HIV epitopes or different viral vectors will do some magic.
On immunization, HIV-derived peptide will be presented to antigen presenting cells. Antigen presenting cells will activate HIV-peptide specific CD4 or CD8 T cells via MHC class II or class I molecules. After initial activation, a small number of T cells will remain as memory T cells and act quickly on their second encounter of the same antigen. This is the immunological basis for the cell mediated (T cells mediated) vaccine. Antibody mediated HIV vaccine is dependent upon generating memory B cells that were pre-exposed to external HIV epitopes, although it requires several critical steps for B cell maturation, which is helped by follicular helper CD4 T cells in several steps.
It is anticipated that pre-clinical experimental trials result in successful boosting of immune responses, whether they are T cell mediated, antibody mediated, or both. If it were not the case, further trials would have been halted at that stage. Due to impressive immune boosting effects during pre-clinical trials, there were high hope that we will be able to obtain a successful HIV vaccine within a few short period of time. Why then, is it so difficult to generate HIV vaccine even after repeated and well-designed trials by many excellent groups for almost two decades? What is (are) the missing element(s)? Can we keep applying the same (or similar) strategy, just changing the minor components, and hope to get a vaccine within a next several decades?
During pre-clinical trials, when the host was not infected by HIV (SIV), all components necessary for an appropriate immune response to any pathogen (including the experimental SIV) remains intact. Once infected with HIV, the normal protective immune response becomes non-functional leading to a systemic immunodeficiency. There could be millions of reasons that can contribute to this. To find a reason or reasons could be very difficult, confusing and time-consuming. At the same time, it will provide a once in a lifetime chance to understand an underlying mechanism(s) on how does an immune system works and how does a vaccine works. I propose here one very apparent reason why do we encounter repeated failures of generating an HIV vaccine. This proposed explanation is well supported by ample experimental data, but not by a current theoretical basis. Our current immunological paradigm could prevent us from moving forward towards generating an effective HIV vaccine. Therefore, the problem could be our knowledge (or misunderstanding, or misconception), instead of the lack of knowledge. It usually takes a lot more time to unlearn, instead of just to learn. We may have to go through both, unlearning and learning.
One very apparent reason:
One of the critical steps for the successful vaccination requires the generation of memory T cells, whether the effect of vaccine is mediated by cytotoxic T cells or by broad neutralizing antibody. The generation and presence of memory T cells enable immune system to react to the previously exposed antigen quickly on the second or repeated exposure of the same antigen. The problem is that the process of generating immunological memory requires effector memory CD4 T cells (I will call them HIV Susceptible CD4 T cells, or HST, which designate CD4 T cells that are susceptible to CCR5 (R5)- tropic HIV). However, during an early period of HIV infection, HIV selectively infect HST and deplete them all in a rapid pace. Therefore, HIV infected individuals will permanently lose HST. Without HST, there is no hope that immune response could be restored. That could have been the case. It is highly likely that HST could expand during vaccination. Expanded HST become ideal and ample targets for CCR5 tropic HIV infection and expansion of virus very early on.
Key words:
HST, AIDS, AIDS vaccine, HIV, cell mediated immune responses, antibody mediated immune responses, viral vectors, immunological memory, CCR5, CCR5-tropic HIV
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