Real Academia Nacional de Medicina

Sesión del día 10 de Febrero de 2004 - Hacia una Vacuna Preventiva del VIH

"Hacia una Vacuna Preventiva del VIH" "Towards an HIV Preventive Vaccine",

Robert C. Gallo





por el Prof. Dr. Robert C. Gallo,

Institute of Human Virology
University of Maryland, Baltimore

Académico Correspondiente Extranjero
Real Academia Nacional de Medicina



It has been clear for the past 15 years that HIV therapeutic eradication by chemotherapy will not likely be feasible for most patients in all of the world and for all patients in the 3rd world, and it has also been clear even longer that an HIV preventive vaccine must be developed. We think that therapy must increasingly be geared toward biological approaches which will be less toxic, affordable, and most importantly feasible for the 3rd world. Such therapeutic approaches will come from basic studies of the biology of HIV and HIV induced disease.

An example of this are studies directed to the identification of naturally occurring HIV suppressive factors. We have now identified 6 such factors. They include 5 ß chemokines and a 6th larger protein currently under investigation. The HIV suppressive activity for 3 is due to interactions with the HIV co-receptors, CCR5, but the mechanisms for the others are more complex and yet to be precisely delineated. It is likely that this area of research will lead to novel therapeutic approaches, and hopefully some may be 3rd world applicable.

Taking advantage of new information on the structure of the HIV gp120 envelop, and the evidence that after gp120 binds to CD4 it conformationally changes, allowing for its interaction with chemokine receptors to initiate cell entry, A. DeVico in our group has prepared a gp120 – CD4 complex which induces neutralizing antibodies with broad reactivity against primary isolates. These preliminary results offer new possibilities not only as a candidate preventive vaccine but also for therapy particularly when HIV titers are not high. This is a therapy that could be applicable for the 3rd world.

An entirely different approach has come from studies of HIV pathogenesis. It is evident that the “faucet drain” models of HIV infection, cell killing, and eventual CD4 T cell depletion are both inaccurate and highly simplistic for many reasons, but mainly because they do not consider the overwhelming evidence that indirect effects of HIV infection are important and possibly even paramount to HIV pathogenesis. These include a diminished hematopoietic generative capacity and the death or malfunction of uninfected “by-stander” cells. Regarding the later: collaborative studies with D. Zagury (Paris) and A. Burny (Brussels) have led us to propose that the HIV Tat protein may be one important element in these phenomena. Not only is Tat an essential regulator of HIV infection in an infected cell, but also released extracellular Tat exerts an effect on uninfected cells which contributes to viral spread and to immune suppression. The immune suppression effect of Tat is partly due to the induction of IFN-a, which is excessively produced in HIV infected persons, and at high levels is itself immunosuppressive. However, extracellular Tat also directly impairs viability of uninfected T cells and facilitates HIV spread by upregulation of HIV co-receptors. We propose vaccinating (2 – 3 times/yr.) with inactivated Tat and IFN-a. This is another therapeutic approach that should be applicable to the 3rd world in terms of feasibility and lack of toxicity.

Our strategy for an HIV preventive vaccine (see also report by George Lewis), is based on these principles:

(1) Complete protection (CP) (sterilizing immunity) is and should remain the goal.

(2) To obtain CP we need to focus on blockade of HIV entry, and currently we know of only two mechanisms to do this induction of: a) neutralizing antibodies and b) natural inhibitors of HIV such as some chemokines. We do not yet know how to induce the HIV suppressive factors, but vaccine candidates should be tested (empirically) to determine which are the best ones that can achieve this.

The recently developed complex of gp120 – CD4 has achieved low but significant broad neutralizing anti-HIV antibodies – as noted above.

(3) Mucosal immunity, targeting dendritic cells, oral delivery, low cost, and thermostabile delivery systems are all desirable or necessary and can be achieved with the attenuated Salmonella system (see George Lewis’ report). These are now undergoing testing.

(4) An inactivated form of Tat. The rationale for including Tat (Toxoid) is described above.

In summary: We cannot depend on current combination chemical anti-HIV therapy for the 3rd world and probably not even for the industrial world. New approaches are needed. Hopefully, they will include therapies that are biological, non-toxic, and feasible forms of therapy. These will come out of basic studies of the biology of HIV.

Preventive vaccines in our view should achieve sterilizing immunity. This “holy grail” may be achievable by vaccines which induce appropriate neutralizing antibodies and augment production of naturally occurring HIV suppressive factors some of which (like neutralizing antibodies) block HIV entry into cells, which is exactly what is needed for a preventive vaccine.