Comments on cell systems, interferon-γ and HIV1

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60th F O R U M I N I M M U N O L O G Y

References

II. Cell lines vs. p r i m a r y cells and interferons

(1) Szebeni J. et al. (1991), J. Virol., 65, 6362-6264. (2) Francis M. and Meltzer M.S. (1993), J. lmmunol., 151, 2208-2216. (3) Gessani S. et al. (1994), J. Virol., 68, 1983-1986. (4) Kombluth R.S. et al. (1990), AIDS Res. Hum. Retr., 6, 1023- 1026. (5) Baca L.M. et al. (1994), J. Leuk. Biol., 55, 299-309.

Gessani and colleagues make a clear-cut dist i n c t i o n c o n c e r n i n g the role o f i n t e r f e r o n s as r e g u l a t o r s o f H I V r e p l i c a t i o n b e t w e e n results obtained in cell lines and those obtained in primary MDM cultures. The general problem of the u s e o f c e l l l i n e s vs p r i m a r y c e l l s g o e s b e y o n d the e f f e c t s o f i n t e r f e r o n s , and can be a p p l i e d to v i r t u a l l y all c y t o k i n e s and s e v e r a l other areas o f e x p e r i m e n t a t i o n . W e feel differently from Gessani and colleagues, as described in detail in our article in this issue. In particular, interferons in HIV infection represent an e x a m p l e o f e s s e n t i a l l y g o o d c o n c o r d a n c e between results obtained in cell lines and primary cells, i.e. suppression of virus replication observed with IFN~/[~; d i c h o t o m o u s results o b s e r v e d with IFNy. Contrasting findings are reported in this issue on w h e t h e r IFN e x e r t s u p p r e s s i v e e f f e c t s in p r i m a r y m o n o c y t e - d e r i v e d m a c r o phages that had already been infected with HIV in vitro (Kornbluth et al. vs G e n d e l m a n et al.), or w h e t h e r g p l 2 0 i n d u c e s IFN p r o d u c t i o n in n o r m a l m a c r o p h a g e s (see G e s s a n i e t a l . vs. Lauret et al.) H o w e v e r , the impaired expression o f IFNc~ d e s c r i b e d b o t h in in v i t r o i n f e c t e d M D M and e x v i v o in P B M C obtained from HIVinfected individuals is also observed in chronically infected U1 cells when c o m p a r e d to their uninfected counterparts, as here reported by Lau and c o l l e a g u e s . Thus, cell lines can be useful and reliable indicators o f regulatory effects, at least in some well defined and controlled exper i m e n t a l c o n d i t i o n s , and m a y allow f o r m o r e rapid d e v e l o p m e n t o f useful intervention strategies against HIV infection. An example is provided by Lauret and colleagues, where cell lines a l o n g with p r i m a r y cells w e r e u s e d as m o d e l systems for testing the in v i t r o e f f i c a c y and the fine mechanisms o f action o f cells p e r m a n e n t l y transduced with an IFN~ gene e x p r e s s i o n system.

C o m m e n t s on cell systems, interferon- 7 and HIV1 G. Poli et al. I. The role o f l F N y re-visited

Emilie, Romagnani, Vyakarnam and colleagues discuss their results within the framework o f the h y p o t h e s i s that a d y s r e g u l a t i o n o f TH0, T. 1, and T n 2 subsets of CD4 ÷ T cells and relateoPcytokine profiles may occur and play a role in the p a t h o g e n e s i s o f HIV disease and AIDS. A c o m m o n view between the first two groups is that IFN 7 may play an important role as a negative regulator of HIV expression in vivo, both in the l y m p h nodes ( E m i l i e ) and in i n f e c t e d T cells undergoing T H 1 differentation, a condition that appears to be less e f f i c i e n t in s u p p o r t i n g HIV replication, as reported by both Romagnani and V y a k a r n a m . In this r e g a r d , it is i m p o r t a n t to remark that the literature on the in vitro effects of IFNT, unlike IFNct/-I], has not provided univocal evidence for a suppressive role in virus expression. Both suppressive and inductive effects o f I F N y h a v e b e e n d o c u m e n t e d in p r i m a r y and i m m o r t a l i z e d m o n o c y t i c cells, and a p o s i t i v e autocrine/paracrine effect of this lymphokine was s u g g e s t e d during in v i t r o i n f e c t i o n o f p r i m a r y CD4 ÷ T cells by Vyarkarnam and colleagues in 1990, a f i n d i n g that o u r g r o u p has r e c e n t l y c o n f i r m e d in the majority of the PBL donors tested. W e h a v e also o b s e r v e d , h o w e v e r , that in approximately one third/one fourth of the donors, neutralization o f the endogenous IFNy effect led to either no effect or increased virus production, similar to the findings o f R o m a g n a n i and colleagues discussed here. Thus, IFNy may act as a negative or positive regulator of HIV replication as a function o f variables which remain essentially unknown, but appear linked to d o n o r - t o donor variation, experimental conditions, or type of functional T-cell infected. It is also possible that factors c o e x p r e s s e d t o g e t h e r with IFN 7 or induced as a consequence of the secretion o f this lymphokine may account for some of these apparently discrepant findings.

Role of cytokines in A I D S : still a challenge R.S. Kornbluth et al.

With the onset of the AIDS pandemic, it initially appeared to be fortuitous that HIV affects cells which were already under intensive scrutiny by immunologists. Unfortunately, like the blind men touching the elephant, our previous knowledge has served to bias our understanding of this virus. For example, it was initially thought that viral latency in T cells was the molecular basis for clinical l a t e n c y in a s y m p t o m a t i c H I V - i n f e c t e d individuals. Later, Pantaleo et al. (1) and others