Grand Challenges in the Immunology of HIV and AIDS

Abstract

After the first reports of patients with AIDS in 1981, the discovery in 1983 of HIV as the etiological agent that causes AIDS and in 1984 of the CD4 protein as the main receptor for the virus our views on HIV pathology have been quite straightforward. Apparently HIV infects CD4+ human cells, which are mainly T helper cells, and in vitro studies show that these cells die in the course of a productive HIV infection. Thus, HIV is cytopathic for CD4+ T helper cells and this relates directly to very low CD4+ T helper cells in patients that present with AIDS symptoms and to the progressive loss of these cells in the course of HIV infection to AIDS. Indeed, in HIV infection the degree of depletion of CD4+ T cell numbers is since these days used as the main marker of disease progression (Fauci et al., 1996). This cytopathic model of AIDS pathogenesis has been boosted by two additional observations of very different kinds. First, Ho et al. (1995) showed the true viral dynamics of HIV infection, making it clear that even in asymptomatic individuals daily production of HIV is very high, at least in the order of 10 (Grossman et al., 2002) viral particles per day, with a RT error rate that creates HIV tremendous variation and allows for rapid escape from drug and immune pressure. In addition, these authors reported high CD4+ T cell death rates and compensatory production of these cells which exhausts the immune system eventually depleting CD4+ T cells, the cause of AIDS. Second, in 1996 formal molecular proof was reported for two distinct co-receptors of HIV (Cocchi et al., 1995; Feng et al., 1996) that explained the observation of HIV variants with different cytopathicity and with different cellular tropism (Tersmette et al., 1989; Koot et al., 1993; Connor et al., 1997). Although in both immunology and virology there were problems regarding this cytopathic account of HIV/AIDS, not in the least because of the lack of a better comprehensive model, until very recently it has been the dominant view in textbooks and the literature.