From: bigoldberg@igc.apc.org (Billi Goldberg)
Newsgroups: sci.med.aids
Subject: AZT Inhibits T4 Cell Proliferation
Date: 3 Oct 92 14:56:54 GMT
Organization: unspecified
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6270

More on AZT and the immune system.

Fauci in an unpublished article, apparently has reported on potential 
mechanisms for the functional and quantitative depletion of CD4+ T 
lymphocytes. These mechanisms are HIV-mediated direct cytopathicity, 
HIV-mediated syncytia formation, virus-specific immune responses (HIV 
specific cytolytic T lymphocytes, ADCC, NK cells), autoimmune 
mechanisms, anergy caused by inappropriate cell signaling, 
superantigens, apoptosis (programmed cell death). Fauci, so it has been 
said, also supports lymph node destruction caused by HIV and HIV-  
immune complexes beaded on follicular dendritic cells as the triggering 
factor in the crisis or last stage of AIDS.

In the article by Heagy (below), it is shown that AZT is anti-        
proliferative to T lymphocytes (fast-replicating cells) in vitro. If 
this is so in vivo, then helper T lymphocytes would be unable to 
proliferate in antibody responses (Th2) thus inhibiting the production 
of autoantibodies (autoimmunity) by B cells and plasma cells against 
infected T4 cells. Therefore, destruction of infected T4 cells in the 
blood would not be accomplished since such destruction by ADCC and 
complement requires production of antibodies and opsonization. Also, 
destruction of infected self-cells by cytotoxic lymphocytes (CTL) and 
natural killer (NK) cells would be impaired since such systemic 
responses requires helper T4 cell proliferation for initiation.

Since infected T4 cells are not being cleared, this would account for 
the transient rise in peripheral blood T4 cells seen in many AZT users 
at the beginning of this treatment.

Psoriasis, a skin disease, caused by overproliferation of epidermal 
cells has been shown to be controlled in AZT users. It appears that at 
least 800 mg of AZT per day is required to control psoriasis. When AZT 
is discontinued, the psoriasis returns. Since this overproliferation is 
probably orchestrated by an immune system response, it seems likely that 
the inability of helper T cells to proliferate would allevate this 
condition.
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Heagy W; Crumpacker C; Lopez PA; Finberg RW.                           
Inhibition of immune functions by antiviral drugs.                      
Journal of Clinical Investigation, 1991 Jun, 87(6):1916-24.             

Abstract: 
Immune functions were evaluated in vitro for PBMC isolated from 
healthy donors and cultured with the antiviral agents, 3'-azido-3' 
-deoxythymidine (AZT), ribavirin, ganciclovir, 2'3'-dideoxyinosine 
(ddI), or acyclovir. To identify methods for assessing the effects of 
antiviral drugs on immune cells, the PBMC response to mitogens, Con A, 
or phytohemagglutinin was evaluated from measurements of [3H]thymidine 
and [14C]-leucine incorporation, cell growth, cellular RNA, DNA, and 
protein levels, and the PBMC proliferative cycle (i.e., progression from 
G0----G1----S----G2 + M). At clinically relevant concentrations, AZT, 
ribavirin, or ganciclovir diminished PBMC responsiveness to mitogen. The 
numbers of proliferating cells in G1, S, and G2 + M phases of the cell 
cycle, DNA content, and [3H]thymidine uptake were decreased in cultures 
treated with AZT, ribavirin, or ganciclovir. AZT or ribavirin but not 
ganciclovir reduced RNA and protein in the cultures and inhibited cell 
growth. Whereas AZT, ribavirin, or ganciclovir were antiproliferative, 
ddI or acyclovir had little, if any, effect on PBMC mitogenesis. The 
inhibitory effects of antivirals on immune cells may contribute to the 
immune deterioration observed in patients following prolonged use of the 
drugs.
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Newsgroups: sci.med.aids