Immunological and virological effects of long term IL-2 therapy in HIV-1-infected patients
AIDS 2001, 15:1729-1744 - Research Letters
Commentary from Jules Levin: WHAT ARE WE GOING TO DO WITH IL-2?
Here is another pilot study suggesting a potential usefulness and benefit for IL-2. But will this study be followed up with further research to explore this use?
IL-2 can be difficult to tolerate. The question is – is IL-2 effective and useful enough for some patients. So far, researchers have not been able to clearly identify situations in which we can see for sure the benefit of IL-2. IL-2 can increase CD4s suggesting it can be useful for patients with low CD4s who are able to achieve undetectable viral load with HAART but are unable to increase CD4s. So, for the patient with undetectable viral load on HAART but with only 150 CD4s, IL-2 may be useful in raising CD4s over 200 or perhaps higher, and thus having a potentially protective effect against opportunistic infections. Even though French doctors use IL-2 in this way this approach has not received overwhelming acceptance here in the US. We have not been able to prove that CD4 increases from IL-2 are as beneficial as CD4 increases from HAART. There is some controversy that IL-2 induced CD4 increases are not as effective in improving the immune system as HAART or ART induced CD4 increases. Studies suggest that IL-2 induced CD4 increases are effective, but there are doubters. Two large international studies are ongoing to try to prove that IL-2 induced CD4 increases are beneficial, as beneficial as ART induced CD4 increases. In the meantime, there are a number of potential uses for IL-2 but not much attention is given to researching these potential uses. Periodically, you will see a study like this one which suggests a utility and benefit from IL-2, and this study suggests an interesting use of IL-2, but usually the study is merely a pilot study and needs further follow-up.
Brief Article Summary:
We report the long-term outcome of 27 HIV-infected patients treated for over 3 years with IL-2 and binucleoside analogues. These patients experienced a sustained increase in CD4 cells and a decrease of proviral DNA with infrequent IL-2 cycles. In three cases, virus could not be isolated from activated peripheral cells. A high frequency of HIV-1-specific memory CD4 T cells was found
in the patients studied. IL-2 maintains specific effector cells and reduces the pool of infected cells in patients, albeit treated only with binucleosides (2 nukes).
Commentary: The authors are suggesting despite low viral load in plasma being present viral load does not increase perhaps because the presence of low level HIV stimulates the immune system (HIV specific CD4s and CD8 memory cells) to exert some control over HIV replication.
HIV-infected patients treated with multidrug highly active antiretroviral therapy (HAART) including a protease inhibitor may experience a prolonged suppres-
sion of plasma viraemia and a dramatic reduction of the incidence of AIDS events [1]. However, the use of these combinations is not without drawbacks, such as adherence, side-effects and viral resistance. Furthermore, the restoration of HIV-specific immune responses in these patients remains incomplete. Therefore, therapy regimens that reduce the viral load
but maintain or re-stimulate HIV-specific immune responses might be beneficial.
We have previously shown in a randomized study [2] that one year of intermittent subcutaneous or continuous intravenous IL-2 therapy induces a substantial
expansion of CD4 T cells in patients treated with two nucleoside reverse transcriptase inhibitors (NRTI; zidovudine and didanosine). We report here, in an open-label observational study, the long-term outcome of 27 patients who completed the randomized phase of the study and accepted extended follow-up. The global median follow-up was 41 months (range 28-49). Before any treatment, the mean CD4 cell count/mm 3 was 428 (range 280-531), the geometric mean plasma HIV-RNA level (branched DNA test) was 17,000
copies/ml (range , 50±255 850), and all patients but one had detectable plasma HIV-RNA levels. All patients started a combination of two NRTI and received
seven intermittent 5 day subcutaneous (4.5 MIU twice a day; n =16) or continuous intravenous (12 MIU/day; n =11) IL-2 cycles, every 8 weeks, during the first year.
After year one, subcutaneous IL-2 cycles were administered as needed to maintain the CD4 cell response (80% increase above baseline). The mean CD4 cell count/mm 3 was 1052 (range 347-2132) at month 12 and 1016 (range 573-1836) at last assessment. During the follow-up, only 60% of patients needed IL-2 cycles. A median of two IL-2 subcutaneous cycles was administered. No specific characteristics of the group of patients who did not require IL-2 during the follow-up were found. The mean plasma HIV-RNA level was 240 copies/ml (range , <50 to 51,433) at month 12 and 350 copies/ml (range , <20-8100) at last assessment. At the last assessment 10 out of 27 patients had plasma HIV-RNA levels below 20 copies/ml. This resulted from therapy with two NRTI, which was maintained in the majority of patients, except in four out of 27 cases who received HAART. No AIDS-related events occured throughout the study. These results indicate that a sustained immunological effect of IL-2 could be obtained in the long term, while HIV-1 viraemia is controlled in patients despite a treatment with a less optimal antiviral regimen.
It has been reported that in the absence of HAART IL-2 therapy transiently stimulates HIV-1 replication. The significance of the low level of virus replication in vivo is unclear, and IL-2 may thereby potentially increase the number of cellular preys for the virus. Therefore, we were interested to assess the HIV-1
reservoir in our patients [3]. Before treatment, the median proviral DNA copies/10 6 peripheral blood mononuclear cells (PBMC) was 460 (range 110-4600),
which decreased to 290 (range 50-1500) at month 12 and 110 (range 4-1250) at last assessment. This corresponds to a -0.37 and -0.63 log10 copies (range
-0.24 to -1.46) median decrease from baseline at month 12 and at last assessment, respectively (Wilcoxon test P=0.001) (Fig. 1a). Similarly, when expressed per 10 6 CD4 T cells, a -0.71 log10 (range -0.56 to -1.62) decrease of proviral DNA from baseline was noted. Cell-associated HIV-1 RNA was detectable in all cases (median 70 copies/10 6 PBMC; range 2-571). At last assessment, the levels of cell-associated viral RNA and proviral DNA were highly correlated ( r = 0.85, P <0.0001) (Fig. 1b). Five patients treated with two NRTI had less than 10 copies of viral RNA/ 10 6 PBMC (Fig. 1b), which was stable when studied twice (one case) or thrice (three cases) at 6 month intervals. We addressed the question of the competence of HIV replication in latently infected cells in four of these patients, as previously described [4]. A total of 25-145 x 10 6 CD8 T cell-depleted PBMC populations were stimulated in vitro. In three patients p24 CD4+CD69+T cells was 2.29% (median 1.35%). The mean (range) frequency of specific CD4 T cells producing TNF-á or IL-2 was quite high, because it represented 0.76% (0±6.97%) and 0.29% (0-1.73%) of total CD4 T cells, respectively. These frequencies were significantly higher than those found for a control group of 12 patients with comparable mean CD4 T cell counts, treated with HAART for a mean duration of 20 months (Fig. 2). These data confirm that the antigen and HIV-RNA levels were below the limit of
detection (20 copies/ml) (Table 1). These results indicate that long-term IL-2 therapy may lead to a very low level of the pool of CD4 T cells harbouring
replication-competent HIV.
The persistence of HIV-1-specific immune responses in patients in the chronic phase of the disease appears to be dependent on the level of antigenic stimulation, which declines during HAART [5]. Using a sensitive assay allowing the detection of cytokine production after a short in-vitro antigenic activation, we found that HIV-1-specific CD4 memory T cells were detectable ex vivo in 12 IL-2-treated patients studied at last assessment. Indeed, the global mean frequency of frequency of virus-specific CD4 effector T cells is low under HAART [5], and they reveal that IL-2 therapy combined with binucleosides preserves these effectors. We show here that a `maintenance' IL-2 regimen, with manageable toxicity, may lead to a sustained increase in CD4 T cell counts, preservation of HIV-specific immunity in patients, albeit treated only with binucleosides. This therapy regimen may thus spare the use of HAART.
Authors:
Marie-Lise Gougeon a, Christine Rouzioux b, Isabelle Liberman a , Marianne Burgard b , Yacine Taoufik d , Jean-Paul Viard c , Kheira Bouchenafa e , Cathe- rine Capitant e , Jean-FrancË ois Delfraissy d , the ANRS 048 Study Group and Yves Levy f , a De partement SIDA et ReÂtrovirus, Institut Pasteur, 25-28 rue du Docteur Roux, 75724 Paris Cedex 15, France; b Service de Virologie, and c Service d'Immunologie Clinique, CHU Necker- Enfants Malades, 149-161 rue de SeÁ vres, 75743 Paris Cedex 15, France; d Service de Me decine Interne, CHU
Kremlin BiceÁ tre, 94 Le Kremlin BiceÁ tre, France; e INSERM SC10, 16 avenue Paul Vaillant Couturier, 94807 Villejuif, France; and f Service d'Immunologie Clinique, Hoà pital Henri Mondor, 51 avenue du MareÂchal de Lattre de
Tassigny, 94010 Creteil Cedex, France.
References
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2. Levy Y, Capitant C, Houhou S, et al. Comparison of subcutaneous and intravenous interleukin-2 in asymptomatic HIV-1 infection: a randomised controlled trial. ANRS 048 study group. Lancet 1999, 353:1923-1929.
3. Burgard M, Izopet J, Dumon B, et al. HIV RNA and HIV DNA in peripheral blood mononuclear cells are consistent markers for estimating viral load in patients undergoing long-term potent treatment. AIDS Res Hum Retroviruses 2000, 16:1939-1947.
4. Lambotte O, Taoufik Y, de GoeÈr MG, Wallon C, Goujard C, Delfraissy JF. Detection of infectious HIV in circulating monocytes from patients on prolonged highly active antiretroviral therapy. J Acquired Immune Defic Syndr 2000, 23:114-119.
5. Pitcher CJ, Quittner C, Peterson DM, et al. HIV-1-specific CD4 T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nat Med 1999, 5:518-525.