AIDSWEEKLY Plus, 20 May 1996 issue; Published by Charles Henderson, Publisher. Editorial & Publishing Office: P.O. Box 5528, Atlanta, GA 30307-0528 / Telephone: (800) 633-4931; Subscription Office: P.O. Box 830409, Birmingham, AL 35283-0409 / FAX: (205) 995-1588
Daniel J. DeNoon, Senior Editor

It works - but how?

The success of an attenuated SIV vaccine in monkeys has U.S. researchers arguing over whether an attenuated HIV vaccine could ever be safe enough for humans.

Meanwhile, French researchers Olivier Benveniste and colleagues of the Institut Paris-Sud sur les Cytokines have been looking to these studies for clues to AIDS pathogenesis - and to vaccine development.

Why, they asked, doesn't the attenuated vaccine cause disease in monkeys?

The answer appears to lie in two key differences: while nef-deleted SIV elicits several T-cell cytokines in the context of low virus burden, pathogenic SIVmac251 elicits almost no T-cell cytokines in the context of high virus burden.

"Our study suggests that an immune response dysfunction may occur early during pathogenic SIV infection in macaques, in a high virus burden context, before clinical events," Benveniste et al. wrote ("Comparative Interleukin (IL)- 2/Interferon (IFN)-Gamma and IL-4/IL-10 Responses During Acute Infection of Macaques Inoculated with Attenuated nef-Truncated or Pathogenic SIVmac251 Virus," Proceedings of the National Academy of Sciences, 1996;93:3658-3663).

"Weak responsiveness, immune paralysis or anergy, well known to be implicated in the ultimate stage of AIDS pathogenesis, may also be present shortly after infection by pathogenic virus and therefore may govern the quality of the subsequent immune responses."

The researchers used a semiquantitative polymerase chain reaction (PCR) assay to monitor T-cell cytokines in eight cynomolgus macaques experimentally infected with a pathogenic primary isolate of SIVmac251 and in four additional macaques inoculated with a nef-truncated molecular clone of SIVmac251.

They looked specifically at T-cell cytokines because of the current debate over whether there is a switch from T- helper type 1 (Th1)-mediated immune responses (characterized primarily by cellular immunity) to Th2-mediated responses (characterized primarily by humoral immunity) during progression to AIDS.

Benveniste therefore evaluated levels of the Th1 cytokines interleukin 2 (IL-2) and interferon (IFN) gamma and of the Th2 cytokines IL-4 and IL-10.

"No type 1 or type 2 T-helper response was seen clearly after inoculation of the pathogenic virus," they reported. "On the other hand, infection with the attenuated clone led to an overexpression of both IL-2/IFN-gamma and IL-4/IL-10."

This led the researchers to conclude that the cytokine profile of the animals receiving attenuated virus was neither Th1 nor Th2 but Th0: precursor T cells producing both types of cytokines.

"The main finding of this study is that monkeys infected by the attenuated nef-truncated virus showed enhanced levels of IL-2, IL-4, and IFN-gamma mRNAs early during infection, whereas monkeys infected by the pathogenic SIVmac251 isolate did not," Benveniste et al. concluded.

"The lack of expression of these cytokines in monkeys infected with the pathogenic primary isolate may reflect early T-cell immunodeficiency, since IL-2 and IL-4 are essentially secreted by T-helper cells, whilst IFN-gamma is secreted by these and other cell types."

The researchers were struck by their observation that one of the "striking resemblances" between early and late stages of HIV (and SIV) disease is elevated viral load.

"One may then hypothesize that the immune unresponsiveness observed may be linked to the presence of high viral burdens rather than being secondary to the dramatic loss of CD4(+) T cells or loss of various immune functions," they wrote. "Accordingly, the infection by the nef truncated clone leads to lower viral loads, which may also explain its attenuated phenotype."

Benveniste et al. concluded that the macaque/SIVmac251 model can not only shed light on AIDS pathogenesis, but also provide clues for vaccine development.

This work was supported by the Agence Nationale de Recherches sur le SIDA (Paris), the Association pour la Recherche en Neurovirologie (Paris), the European Concerted Action on Animal Models for AIDS (Gottingen, Germany), and the European Vaccine against AIDS program (Hertfordshire, United Kingdom).

The corresponding author for this study is Olivier Benveniste, Service de Neurovirologie, Commissariat a l'Energie Atomique, Direction des Sciences du Vivant, Departement de Recherches Medicale, Centre de Recherches du Service de Sante des Armees Emile Parde, Institut Paris-Sud sur les Cytokines, 60-68 Avenue de la Division Leclerc, B.P. 6, 92265 Fontenay aux Roses, Cedex, France.

Copyright (c) 1995 - Charles Henderson, Publisher. All rights Reserved. Permission to reproduce granted to AEGIS by Charles W. Henderson. Authorization to reproduce for personal use granted granted by C. W. Henderson, Publisher, provided that the fee of US$4.50 per copy, per page is paid directly to the Copyright Clearance Center, 27 Congress Street, Salem, Massachusetts 01970, USA.

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Copyright © 1996 - Charles Henderson, Publisher. All rights Reserved. Permission to reproduce granted to AEGIS by Charles W. Henderson. Authorization to reproduce for personal use granted granted by C. W. Henderson, Publisher, provided that the fee of US$4.50 per copy, per page is paid directly to the Copyright Clearance Center, 27 Congress Street, Salem, Massachusetts 01970, USA.