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HIV vaccine development—
The hurdles faced by scientists

The reasons why we still do not have a vaccine to stop the spread of HIV are complex and varied, and go beyond the scientific hurdles. But these obstacles are themselves immense.

Effective vaccines for some infectious diseases work because they present the immune system with antigens to which antibodies are produced. However, many researchers do not believe that merely inducing antibodies against HIV would prevent the virus from establishing an infection.

Such pessimism for an antibody-based approach stems in part from what has been learned about the role of antibodies against HIV on the natural course of an infection. Within weeks of HIV infection, the amount of virus in the blood (viral load) reaches extremely high levels. Several weeks later, the viral load falls dramatically to a much lower level. Only after this reduction has occurred do antibodies that effectively neutralize HIV appear in the blood. This suggests that some other kind of immune reaction is responsible for the initial control of viral load. Furthermore, neutralizing antibodies in the blood of infected individuals do not seem to greatly influence the subsequent course of infection (i.e., the length of time before CD4 counts fall and AIDS-defining symptoms are seen in the absence of treatment).

Finding correlates of protection

If neutralizing antibodies will not do the trick, some other immune response must be employed. A wide spectrum of possible antiviral responses are available to the immune system, and scientists have been attempting to correlate them with protection against HIV infection in animal models. Unfortunately, in part because these responses can be difficult or impossible to measure, these so-called "correlates of protection" are still undefined.

For example, antibodies produced at mucosal surfaces—as opposed to antibodies circulating in the blood—may have more impact on HIV transmission, because the majority of new infections occur at the mucous-coated surfaces of the uro-genital tract and the gastrointestinal tract. Much work has been going into the development of a "mucosal" HIV vaccine, but since there is little precedence in vaccinology for such approaches, researchers still lack basic information about them.

Many scientists believe that the dramatic albeit incomplete immune control of HIV seen shortly after infection (as discussed above) is due to the activity of CD8 cells, sometimes referred to as CTLs (though the terms are not synonymous). Could CD8 cellular activity represent a necessary correlate of protection? CD8 cells in fact perform a number of antiviral activities, but whether these cells can sufficiently protect against infection remains an open question. Still, researchers have been paying greater attention to the effects of HIV vaccine candidates on CD8 cell functioning.

Other immune responses might also have an impact on HIV infection. Many kinds of immune cells secrete chemicals into the blood that strongly affect the response to microbial infections. One such class of chemical, called chemokines, has been associated with protection in animal models of HIV vaccine candidates.

HIV vaccine development suffers from an incomplete understanding of how these various immune responses can impact HIV transmission.

HIV diversity yet another hurdle

The global epidemic involves not a single virus, but a genetically diverse family of HIV. It remains unknown how this will impact vaccine development. The predominant type, or "clade", of virus in North America and Europe is clade B, but in many Third World countries, non-B clades predominate. Clade C, in fact, now is responsible for the majority of new infections. For this reason, some scientists have been calling for a greater allocation of resources towards the development of a vaccine appropriate for protecting against transmission of clade C virus.

Can an HIV vaccine be developed that protects against multiple clades of virus? Some experimental vaccine candidates are capable of inducing immune responses effective against HIV of several clades—so called "cross-clade" protection. But without knowing what constitutes the correlates of protection against HIV infection, one cannot be certain in advance how cross-clade protection can be achieved in practice.

Attacking the immunosuppression

The entire problem can be viewed at another level. What if there are immune responses that could protect against infection, but HIV prevents them from being activated? Even within the first years of the epidemic, it was becoming clear that the impairment of the immune system can be out of proportion to the loss of immune cells. Immunosuppression by HIV is not just a matter of how many cells it kills, it seems.

Data have been accumulating to suggest that the HIV protein Tat is a toxin that is at least partially responsible for this immunosuppression. In infected individuals, Tat can be found dissolved in the blood, independent of the virus. Though probably still a minority view amongst researchers, it has been suggested on this basis that Tat will be a necessary component of a preventative HIV vaccine. The argument (still controversial) is that the long-sought immune correlate of protection against HIV is inhibited by Tat. If so, then a Tat vaccine might permit these responses to emerge. The vaccines against several infectious diseases actually do consist of inactivated toxins produced by the microbes, so that this approach has some precedence.

Prospects

The very nature of HIV infection requires new thinking about vaccine approaches. HIV presents issues that have not necessarily been encountered before with other diseases. They will have to be resolved by focused and continued effort.