From Pathogenesis to New Concepts of Therapy.

Robert C. Gallo, MD.

Director, Institute of Human Virology, University of Maryland Baltimore (USA)

HIV pathogenesis involves both direct pathogenic effects on some HIV infected cells and indirect effects on uninfected (bystander cells).  It has been self-evident for almost 20 years that reducing the amount of virus would be beneficial to infected persons, and this was documented by appropriate pharmacological attacks on HIV enzymes since the mid-1990s.  Reduction in HIV levels hinders both the direct and indirect pathogenic effects.

Because of HIV high mutation rates and thus HIV drug escape mutants, long term toxicity with some current protocols, and the desirability of more feasible therapies for patients in developing nations we are in continuous need for new approaches to therapy.  One such approach is blockage of HIV entry.  This can be achieved by targeting any of the major steps involved in HIV entry.  A particularly attractive step to target is CCR5 since: (a) the bulk of HIV variants utilize this receptor, (b) genetic mutations leading to loss of CCR5 are not harmful to modern people, (c) a cellular protein is less variable than a viral protein.  This story began with our observations that CCR5 β-Chemokine ligands (RANTES, MIP-1αlpha, and MIP-1β) were potent inhibitors of HIV and the results of others soon after which provided the mechanism for this effect (by E Berger, P. Murphy, J. Moore, D. Littman and others) when they showed CCR5 to be a second and critical HIV receptor.  Targeting CCR5 with small drugs (agonists or antagonists of these ligands) has already been shown to be effective in patients.  In this report I will show that induction of elevated β-Chemokine ligands for CCR5 is associated with resistance to HIV infection and resistance to progression once infected.  Enhancement of chemokines results in diminished CCR5 and studies from our group (Heredia, Redfield et al) have shown that agents which increase chemokines and diminish CCR5 synergize with drugs which target CCR5 in reducing HIV.  Results with new agents directly targeting CCR5 will also be summarized.

Attempts to diminish the indirect effects of HIV on uninfected (other than by HIV reduction) strictly depend upon our knowledge of pathogenesis.  Pathogenesis studies with D. Zagruy, A. Burny and others led us to conclude that IFN-αlpha is a major factor in the perturbation and premature killing of bystander cells.  A simple and practical approach to diminish this effect is the use of therapeutic vaccines against IFN-αlpha and the HIV Tat protein which is directly involved in promoting the overproduction of IFN-αlpha.