Third International Congress Drug Therapy in HIV Infection 3-7 November 1996 Glasgow, UK

CAN ANTIVIRAL THERAPY RESTORE IMMUNE FUNCTION?

AD Kelleher¹ and DA Cooper^{1, 2
1}Centre for Immunology, St Vincent's Hospital and ²National Centre for HIV Epidemiology Clinical Research, Sydney, NSW 2010, Australia

Int Cong Drug Therapy HIV 1996 Nov 3-7;3:Abstract No. 2.3
AIDS 1996, Vol. 10 (Suppl. 2);S2

Subtle, subclinical deficits in immune function are present early in HIV-related disease. These are evident from minor opportunistic infections, reduced vaccine efficacy of vaccines, and reduced delayed type hypersensitivity (DTH), proliferative and IL-2 responses to recall antigens. Furthermore, recent evidence suggests a progressive loss of CD4+ T-cell receptor repertoire with disease progression.

Therapeutic intervention, even with relatively weak nucleoside anti-retrovirals, has resulted in improvements in lymphocyte function and reductions in immune dysregulation. Recently, we have made a number of observations indicating similar responses following therapy with protease inhibitors as single agents. Increases in CD4+ and CD8+ cell numbers, reduction in the expression of cellular activation markers, increased expression of CD28 on CD4+ cells and increased proliferative responses to mitogen and recall antigens were observed. It was notable, however, that where responses were absent prior to therapy, improvements were small and transient and occurred in a minority of subjects. Furthermore, the great majority of CD4+ cells making up the increase were CD45RO+ cells and Vβ representation was not significantly altered by therapy. These data suggest peripheral expansion of remaining clones but-no generation of naïve CD4+ cells.

The effect of suppressing virus to undetectable levels for extended periods is not known, however two observations would indicate that complete restoration of immune function in persons in whom therapy is commenced in advanced stages of HIV disease may not be possible. Firstly, therapy of late stage disease with a potent single agent results in a shift of the phenotypic and functional profile of a subject's lymphocytes to that characteristic of the asymptomatic phase of the disease, not to that of an uninfected person. Secondly, recently presented data showed that combination therapy which reduced viral load to undetectable levels did not result in proportionally larger CD4+ cell count increases. There was apparently a ceiling to CD4+ cell increase, as if a new set point or limit for CD4+ cell number has been imposed by HIV-infection. Despite apparently "ablative" antiviral therapy CD4+ cell counts increase significantly but do not return to normal levels.

If restoration of lost function of the adult immune system is not possible due to HIV induced deletions of T-cell repertoire then preservation of the immune system needs to be attempted and early institution of "ablative" antiviral therapy provides the opportunity. But to be effective it must be instituted early, prior to the onset of significant deficits.

Presenting author: D A Cooper

1996-11-03
2.3

Originally published in AIDS Volume 10, Supplement 2 and hosted with permission of the publisher Lippincott Williams & Wilkins, 250 Waterloo Road, London, SE1 8RD, UK. Tel: +44 (0)20 7981 0700 Fax: +44 (0) 7981 0701

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