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.

Oral aspirin and ibuprofen increase cytokine-induced synthesis of IL-1 beta and of tumour necrosis factor-alpha ex vivo.

We investigated the effect of oral aspirin and ibuprofen on the ex vivo synthesis of interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-6, tumour necrosis factor-alpha (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) by stimulated peripheral blood mononuclear cells (PBMC) from healthy volunteers. Seven volunteers took 325 mg of aspirin daily for 14 days. Three weeks after ending aspirin medication, ex vivo IL-1 beta and TNF synthesis induced by exogenous IL-1 alpha was elevated threefold compared to the pre-aspirin value (P = 0.01 and P = 0.005, respectively). Using lipopolysaccharide (LPS) as a stimulus, no influence of oral aspirin was observed. The increase in cytokine synthesis did not parallel decreased synthesis of prostaglandin E2 (PGE2). Seven weeks after discontinuation of aspirin, cytokine and PGE-2 production returned to pre-aspirin levels. Another seven volunteers took 200 mg of ibuprofen daily for 12 days. Again, there was no effect on LPS- or Staphylococcus epidermidis-induced cytokine synthesis. However, IL-1 alpha-induced synthesis of IL-1 beta was elevated to a mean individual increase of 538% (P < 0.001) and synthesis of TNF was elevated to 270% (P < 0.001) at the end of ibuprofen medication and 2 weeks after discontinuation of ibuprofen. There were parallel increases in PGE2 and both returned to their pre-ibuprofen levels 5 weeks after stopping. Although inhibitors of cyclo-oxygenase blunt PGE2-mediated symptoms such as fever and pain, we conclude that short term use of either aspirin or ibuprofen results in a 'rebound' increase in cytokine-induced cytokine synthesis that is not observed in LPS-induced cytokines.

Racial differences in social support and mental health in men with HIV infection: a pilot study.

The mediating role of social support in the mental health and behaviours of persons coping with life-threatening chronic illness is of potentially great importance in determining the quality of life of persons with HIV infection (PWHs). As part of a biracial pilot study of the ways black and white men manage the stresses of sexually acquired HIV infection, we have examined the relationship between social support and mental health and behaviours. Forty homosexual/bisexual men (20 white and 20 black) attending a Detroit hospital-based HIV outpatient clinic were recruited for the study and underwent physical and mental health (HSCL-59 and NIMH DIS interview), behavioural and psychosocial evaluations, and a neuropsychologic screening test battery. The black and white men did not differ in terms of age, education, sexual behaviours, physical or mental health status. However, the black men were less likely to be open about their sexuality to their primary social support network, and to report that their social support was less affirmative than did the white men. When correlations between the six-dimensional social support measures (Wortman & O'Brien, 1987) and HSC-L distress scores were examined, both availability of material social support and affirmation were correlated negatively with distress among the white men but positively among the black men. Similarly, the previously observed positive relationship between perceived adequacy of social support and adoption of safer sexual practices was observed among white but not black participants.(ABSTRACT TRUNCATED AT 250 WORDS)