CN103736081A - Application of ONTAK in preparing medicine for eliminating latent HIV (Human Immunodeficiency Virus) - Google Patents

Abstract

The invention relates to a new application of ONTAK, that is, the application of ONTAK in the preparation of drugs for eliminating latent HIV virus. The application of ONTAK to AIDS patients who are effective in long-term ART treatment can increase HIV-specific immune response and activate latent HIV virus, which is beneficial to eliminate latent HIV virus.

Description

Application of ONTAK in the preparation of drugs for eliminating latent HIV virus

technical field

The invention relates to the use of medicine, in particular to the application of ONTAK in the preparation of drugs for eliminating latent HIV virus.

Background technique

Since the discovery of HIV (human immunodeficiency virus) virus, there have been many anti-HIV virus drugs, which can suppress HIV virus to an undetectable level and effectively prevent the occurrence of AIDS-related complications. Due to the existence of latent HIV virus, although the current anti-HIV virus drugs can effectively inhibit the replication of the virus, they cannot completely eliminate the virus. HIV patients cannot stop taking the drug and need to take the drug for life. Latent HIV virus has become an obstacle to the eradication of HIV virus. Studies on latently infected cell models have shown that latent HIV virus is dormant, but has the ability to produce virus once activated. Due to the presence of latent HIV virus, lifelong antiretroviral treatment is required. Lifelong antiviral therapy has many defects, such as drug side effects, drug resistance, and increased economic burden of antiviral therapy. Therefore, it is very urgent to invent drugs against latent HIV virus.

Also try some means to activate and eliminate the medicine of latent HIV virus both at home and abroad. Early use of IL-2-binding CD3 antibodies to activate latent HIV proved ineffective in clearing latent HIV. Recent research has focused on small-molecule drugs that activate latent HIV. Two FDA-approved drugs for the treatment of other diseases, valproic acid (valproic acid) and SAHA (suberoylanilide hydroxamicacid), have been shown to activate latently infected HIV cells in cell models. But clinical trials have shown that it is ineffective in eradicating latently infected HIV. Shan et al found that stimulating HIV-specific CTL responses before activating the latent HIV virus is beneficial to destroy the latent virus [Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, Yang HC, et al. Stimulation of HIV- 1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity2012;36:491-501.].

ONTAK (denileukin diftitox) is produced by Seragen and Eli Lilly, and has been unanimously recommended by the FDA Advisory Committee in the United States for the treatment of relapsed or persistent cutaneous T-cell lymphoma in adults. It has been reported that researchers are working on using this drug for the treatment of other cancers, such as ovarian cancer, breast cancer, and lung cancer, but this drug has not been reported for the treatment of AIDS.

Contents of the invention

The object of the present invention is to provide the application of ONTAK in the preparation of medicine for eliminating latent HIV virus.

In order to solve the above problems, the present invention adopts the following technical solutions:

Application of ONTAK in preparation of medicament for eliminating latent HIV virus.

In the above-mentioned application, preferably, the latent HIV virus refers to the HIV virus that cannot be cleared by antiretroviral drug treatment at present, which is the main reason why AIDS patients cannot stop taking the drug, and the latent HIV virus is in a dormant state. Once activated, it still has the ability to produce virus.

As mentioned above, preferably, the drug for eliminating latent HIV virus is injection or freeze-dried powder.

The beneficial effects of the present invention are as follows: Currently, there is no effective measure against latent HIV virus. At present, researches at home and abroad believe that drugs or targets that activate latent HIV virus and increase HIV-specific CTL responses are effective measures to eliminate latent HIV virus. The researchers of the present invention found that after long-term effective ART (antiretroviral drug) treatment, ONTAK can effectively activate the latent HIV virus, increase HIV-specific CTL response, and reduce the amount of HIV virus. Therefore, ONTAK is an effective measure to eliminate latent HIV virus.

Description of drawings

Figure 1 shows the HIV-specific CTL responses of PBMCs of patients in group a without and after treatment with ONTAK.

Figure 2 shows the HIV-specific CTL responses of PBMCs of patients in group b without and after treatment with ONTAK.

Fig. 3 is the HIV-specific CTL response of PBMCs of patients in group c not treated with ONTAK and after treatment.

Fig. 4 is the activation degree of CD4 cells after PBMCs of patients in group a were not treated with ONTAK and after treatment.

Fig. 5 is the activation degree of CD4 cells after PBMCs of patients in group b were not treated with ONTAK and after treatment.

Fig. 6 is the activation degree of CD4 cells after PBMCs of patients in group c were not treated with ONTAK and after treatment.

Figure 7 shows the levels of HIVp24 in PBMCs of patients in group a without and after treatment with ONTAK.

Figure 8 shows the levels of HIVp24 in PBMCs of patients in group b without and after treatment with ONTAK.

Figure 9 shows the levels of HIVp24 in PBMCs of patients in group c without and after treatment with ONTAK.

Detailed ways

Embodiment 1 ONTAK removes the in vitro experiment of latent HIV virus

(1) Materials

Drug ONTAK was purchased from Seragen and Eli Lilly;

HIV-1gag p24KC57 was purchased from BD (Becton, Dickinson and Company)

Pentamer detection reagent was purchased from Oxford University (Oxford, United Kingdom)

(2) Method

(1) Research objects: 10 untreated AIDS patients (P1-P10) as a group (a), 10 AIDS patients (P11-P20) who have been treated with national first-line anti-AIDS drugs for 1 year as a group (b), A group of 10 patients (P21-P30) who have been treated with national first-line anti-AIDS drugs for 5 years (c);

(2) Separation of PBMCs by density gradient centrifugation;

(3) Cell culture: add ^2x106 cells to each culture well, some of the culture wells use only PBMC, and the other part of the cell wells add 0.1 μg of ONTAK in addition to the same PBMC (that is, add 0.1 μg of ONTAK to the 500ul culture system ONTAK), after 72 hours of culture, detect the cell activation level, HIV-specific CTL level and p24 level in PBMC wells and PBMC wells with ONTAK added;

(4) Flow cytometric analysis: use pentamer to detect the level of HIV-specific CTL, use HLADr and CD38 to detect the level of cell activation, and use HIV-1gag p24KC57 to detect the expression of p24.

(3) Results

The results are shown in Figure 1-Figure 9. From the results in Figure 1, it can be seen that for untreated patients, after treatment with ONTAK, HIV-specific CTL responses are very different among different patients; it can be seen from the results in Figure 2 For patients who have been treated for 1 year, after treatment with ONTAK, HIV-specific CTL responses vary greatly among different patients; from the results in Figure 3, it can be seen that for patients who have been treated for 5 years, after treatment with ONTAK, HIV-specific CTL responses Responses were increased in all patients.

It can be seen from the results in Figure 4 that for untreated patients, after treatment with ONTAK, the activation of CD4 cells is very different among different patients; , CD4 cell activation is very different among different patients; it can be seen from the results in Figure 6 that for the patients treated for 5 years, after ONTAK treatment, the activation of CD4 cells increased in all patients.

It can be seen from the results in Figure 7 that for untreated patients, after treatment with ONTAK, the expression level of HIV-1p24 is very different among different patients; After treatment, the expression level of HIV-1p24 was very different among different patients. It can be seen from the results in Figure 9 that for the patients treated for 5 years, the expression of HIV-1p24 was reduced in all patients after treatment with ONTAK.

From the above results, it can be seen that HIV-specific CTL responses increased in all patients after PBMC treated with ONTAK for 5 years, the activation of CD4 cells increased in all patients, and the expression of HIV-1p24 increased in all patients. There is a reduction. It shows that ONTAK can activate and eliminate latent HIV virus after effective long-term ART (antiretroviral drug) treatment, and it is an effective measure to eliminate latent HIV virus.

Claims (3)

1.ONTAK removes the application of hiding in HIV virus drugs in preparation.

2. application as claimed in claim 1, it is characterized in that, the described HIV of hiding virus refers at present can not be by the HIV virus of its removing through antiretroviral drugs treatment, it is the main cause that current aids patient can not drug withdrawal, hide HIV virus in resting state, once activation still has the viral ability of producing.

3. application as claimed in claim 1, is characterized in that, the described removing HIV virus drugs of hiding is injection or lyophilized powder.

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