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Preprint Available: Analysis of Models of HIV Pathogenesis

Russell Anderson rwa at milo.berkeley.edu
Sat Sep 6 10:58:43 EST 1997

Two preprints are now available by electronic mail:

1. Anderson RW. 
Mathematical models of HIV pathogenesis.
Nature Medicine, 3(9):936-7 (1997). 
     [commentary on Grossman and Herberman (1997)]

2. Russell W. Anderson, Michael S. Ascher, and Haynes W. Sheppard 
Direct HIV cytopathicity cannot account for CD4 decline in AIDS
in the presence of homeostasis.  A worst-case dynamical analysis
J. AIDS & Human Retroviruses (in press: 1997)
     [Abstract below]

If you would like to receive a text version of either paper,
please contact me at the address below:

Russell W. Anderson
Smith-Kettlewell Eye Research Institute
2232 Webster Street
San Francisco, CA  94115
Office: (415) 561-1715
FAX:    (415) 561-1610
anderson at skivs.ski.org
rwa at milo.berkeley.edu


The central paradox of HIV pathogenesis is that the viral burden
(either free or cellular) seems far too low to deplete the CD4 
population by direct killing.  Until recently, there were few data which
could be used to critically compare direct and indirect pathogenic 
theories.  Clinical trials with potent new antiviral agents have 
measured important kinetic parameters of HIV infection, including viral 
and infected cell half-lives. This has led to the construction of 
explicit models of direct killing.  Using a worst-case dynamical 
analysis, we show that such cytopathic models are untenable.  
Rates of infected cell removal are orders of magnitude too low to 
significantly suppress steady state CD4 counts in the face of 
lymphocyte replenishment, especially in early infection.  Furthermore, 
the direct cytopathic models, as proposed, predict an extremely 
variable disease course across the broad range of observed
viral burdens (five orders of magnitude), which is inconsistent 
with the relatively small differences in disease progression 
observed between patients.  In contrast, immunological theories 
of pathogenesis, such as homeostatic dysregulation based on 
immune activation, do not suffer from these difficulties
and are more consistent with the natural history of HIV infection.

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