Re-assessing the virological approach to HIV pathogenesis: can it explain AIDS as an immunological disease?

Over 10 years after the discovery of HIV, its molecular virology still fails to explain the clinical immunology of AIDS. The prevailing paradigm of AIDS pathogenesis, called here the "virological hypothesis", argues that viral attributes such as cytopathicity, replicability, syncytiality, cell tropism, emergent virulence, and viral load explain why infection develops to a life-threatening immunodeficiency. However, these attributes-singly and in combination-are shown here to be inadequate to explain the latency, immunological damage, and clinical dynamics of the disease of AIDS. The virological paradigm cannot explain the disease-free period (clinical latency); the mechanism and dynamics of CD4 T cell loss; the reason for the onset of disease at a given time-point; the relationship of CD4 T cell loss to AIDS-type disease; nor the idiosyncratic constellation of immunological and clinical phenomena that comprise AIDS as a unique syndrome. HIV as it is currently understood does not have the virological characteristics necessary to create a disease such as AIDS through direct classical (i.e. cytopathic) mechanisms. It is clear that the pathogenesis of AIDS remains unknown. Therefore, treatment based solely on inhibiting viral mechanisms-as with antivirals-is very likely to be insufficient. In addition, the molecular epidemiology of pathogenesis has been very poor; there is an enormous amount that is not known about the clinical immunology of AIDS, and the central question remains of how CD4 cell loss relates to clinical immunodeficiency. The conclusion drawn is that the virology of HIV has been pursed at the cost of understanding AIDS itself; that an emphasis on AIDS as an immunological disease is long overdue; and that appropriate treatment of AIDS will not be possible until the clinical immunology of AIDS is understood.