From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: Does AZT Suppress CTLs?
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6734
Organization: unspecified
Date: Fri, 8 Jan 93 00:19:35 PST

          ZIDOVUDINE (AZT) AND CYTOTOXIC CD8 T LYMPHOCYTES
                       by Billi Goldberg

Why weren't CD8 counts reported in the primary AZT Clinical Trials 
Groups 016 and 019? Obviously they were done; at the very least, CD4:CD8 
ratios were recorded. Based on a cursory evaluation of the three studies 
shown below, there can be some very significant reasons why this wasn't 
done. It appears that activated cytotoxic T lymphocytes (HLA-DR) showed 
significant decreases both in the Bass et al. and Levacher et al. 
studies. The Levacher study is extremely interesting since it shows a 
transient increase in CD4+ cells at week 12 but a striking decrease from 
baseline of activated T lymphocytes (CD3+ HLA-DR+) at weeks 12 and 24 of 
AZT treatment. The Reddy et al. study also showed decreases in soluble 
CD8 after treatment with AZT.

If activated CD8 T lymphocytes are important in controlling 
intracellular pathogens, especially the HLA-DR subset, any treatment 
such as AZT that surpresses this subset must be questioned. At the very 
least, CD8 subsets should be reported for all clinical trials of 
antivirals that claim efficacy. In my opinion, these studies provide 
support for the hypothesis that AZT does nothing more than suppress the 
immune response resulting in increases of infected CD4 cells.
================================================================   
Bass HZ; Hardy WD; Mitsuyasu RT; Wang YX; Cumberland W; Fahey JL. 
Eleven lymphoid phenotypic markers in HIV infection: selective changes 
induced by zidovudine treatment. Journal of Acquired Immune Deficiency 
Syndromes, 1992, 5(9):890-7. 

Abstract: HIV infection induces substantial changes in the expression of 
many lymphocyte phenotypic markers as well as depletion of CD4 
lymphocyte numbers. A comprehensive study was undertaken to determine 
whether seven lymphocyte phenotypic changes associated with HIV 
infection (increased CD38, HLA-DR, CD57, and CD71 and decreased CD11b, 
CD45RA, and leu-8) are altered by zidovudine (ZDV) administration. 
Levels of the four major lymphoid subsets (CD4, CD8, B, and NK cells) 
and changes in the serum activation markers neopterin and beta 
2-microglobulin (beta 2M) were also measured. Elevated pretreatment 
expression of CD38 and CD71 was reduced significantly toward normal at 2 
weeks by ZDV; however, CD38 and CD71 returned to pretreatment levels at 
different rates. The kinetics of CD38 reduction and the return to 
pretreatment levels were similar to those of serum neopterin and beta 
2M. HLA-DR decreased in many but not all subjects. CD4 lymphocytes 
showed a transient increase, most evident at 8 weeks of treatment. 
Lymphoid phenotypes that did not show significant changes after ZDV 
therapy included CD57, CD11b, CD45RA, and leu-8 markers as well as CD8 
T cells, CD20 B cells, and CD56 NK cells. The fact that some lymphocyte 
phenotypic markers change toward normal with ZDV treatment and others do 
not indicates that complex processes underlie immune perturbations of 
HIV infection. Several phenotypic markers (CD38, CD71, and HLA-DR) that 
are susceptible to short-term effects of ZDV (but with changes that 
differ from CD4 T cell changes) are surrogate marker candidates for 
evaluation in anti-HIV treatment. 
================================================================ 
Levacher M; Tallet S; Dazza MC; Dournon E; Rouveix B; Pocidalo JJ. 
T activation marker evaluation in ARC patients treated with AZT. 
Comparison with CD4+ lymphocyte count in non-progressors and progressors 
towards AIDS. Clinical and Experimental Immunology, 1990 Aug, 
81(2):177-82. 

Abstract: Reductions in the percentage and absolute number of CD4+ 
lymphocytes, as well as abnormally high levels of activated peripheral T 
lymphocytes (CD3+ HLA-DR+ phenotype) and an increased proportion of CD8+ 
cells coexpressing the CD57 surface antigen (involved in natural killer 
activity) have been reported in HIV infection and associated with 
disease progression. We prospectively measured these subsets of 
lymphocytes in 34 patients with advanced AIDS-related complex (ARC) 
treated with azidothymidine (AZT). Peripheral blood lymphocyte 
phenotyping was performed before treatment, then at weeks 12 and 24. A 
striking fall in the proportion of activated T lymphocytes from baseline 
was observed (P less than 0.001) at week 24. In contrast, the percentage 
of CD4+ cells showed a slight and transient rise at week 12 (P less than 
0.05). No modification in levels of CD8+ or CD8+ CD57+ cells was 
detected during the study. Of the 34 patients, 11 developed AIDS, and 23 
remained AIDS-free during 51 weeks of follow-up. Similar patterns of 
change in CD4+ and HLA-DR+ CD3+ lymphocytes were found in the AIDS 
progressors and nonprogressors. Likewise, HIV p24 antigenaemia showed 
parallel decreases in both groups of patients. Although changes in CD4+ 
cells, p24 antigenaemia and HLA-DR-reactive T lymphocytes were not 
predictive of clinical outcome, large differences existed between 
the two groups prior to the initiation of therapy. The short-term onset 
of AIDS was associated with lower CD4+ cell numbers, higher levels of 
serum p24 antigen and a greater proportion of activated T lymphocytes. 
Our results suggest that the possible interest of T lymphocyte 
activation markers, in conjunction with conventional phenotyping, should 
be investigated further.  
================================================================
Reddy MM; McKinley G; Englard A; Grieco MH. Effect of azidothymidine 
(AZT) on HIV P24 antigen, beta 2-microglobulin, neopterin, soluble CD8, 
soluble interleukin-2 receptor and tumor necrosis factor alpha levels in 
patients with AIDS-related complex or AIDS. International Journal of 
Immunopharmacology, 1990, 12(7):737-41. Pub type:  Clinical Trial; 
Journal Article; Multicenter Study. 

Abstract: Circulating HIV P24 antigen, beta 2-microglobulin, neopterin, 
soluble CD8, soluble interleukin-2 receptor and TNF alpha levels were 
measured in 20 patients (9 with ARC and 11 with AIDS) treated with 
azidothymidine (AZT) and in 12 patients (3 with ARC and 9 with AIDS) who 
were in a placebo group. Mean levels of HIV P24 antigen, beta 2-
microglobulin, neopterin and SCD8 decreased significantly (P less than 
0.05) after 12 to 16 weeks of AZT administration. SIL-2R and TNF alpha 
serum levels did not appear to change in association with AZT therapy. 
No changes were observed in the placebo group except that TNF alpha 
levels appeared to increase after 12 to 16 weeks. These results suggest 
that AZT administration may have led to reduced HIV P24 antigen, beta 2-
microglobulin, neopterin and SCD8 mean levels in these patients. 

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