WO2020186573A2

WO2020186573A2 - Method for curing aids or hiv infection

Info

Publication number: WO2020186573A2
Application number: PCT/CN2019/081823
Authority: WO
Inventors: 魏民
Original assignee: 南开大学
Priority date: 2019-03-18
Filing date: 2019-04-08
Publication date: 2020-09-24

Description

A way to cure AIDS or HIV infection

Technical field

The invention belongs to the field of biomedicine and relates to a new method for curing AIDS and HIV-1 infection.

Background technique

AIDS (Acquired Immune Deficiency Syndrome, AIDS) caused by Human Immunodeficiency Virus (HIV) or HIV has been circulating globally for more than 30 years. AIDS is a severe infectious disease. The virus directly attacks the human immune system, causing defects in human immune function, prone to opportunistic infections and tumors, and most of them die. According to UNAIDS (UNAIDS), as of the end of 2017, there were approximately 36.9 million people living with HIV-1 in the world, and approximately 36 million people had died, for a total of approximately 72.9 million. In 2017, about 1.8 million people were newly infected with HIV-1 (http://www.unaid.org). So far, there is still no effective vaccine against AIDS. Although antiretroviral drugs and combined antiretroviral therapy (combined antiretroviral therapy, cART) have made great progress and can effectively control virus replication, they still cannot completely eliminate the virus and cannot cure AIDS. AIDS has caused significant economic losses throughout the world.

In 2014, the United Nations AIDS Program (UNAIDS) set a goal to achieve the 90-90-90 goal by the end of 2020, that is, 90% of HIV-infected persons will be diagnosed and 90% of confirmed HIV-infected persons will receive combined antiretroviral transcription Viral therapy (cART), 90% of patients receiving cART therapy will suppress the HIV virus in the body (http://www.unaids.org). This year, it is 2019. This goal has been achieved in some countries, such as Sweden and the United Kingdom. However, in many countries around the world, this goal has not been achieved ^{[1, 2]} . The next goal set by UNAIDS is to end the AIDS epidemic by 2030. If there is currently no cure, no effective vaccine, and the global 90-90-90 goal has not been achieved, then "end the AIDS epidemic globally by 2030" will be empty talk.

After the introduction and spread of AIDS in my country in the 1980s and 1990s, the incidence of AIDS in China has now entered a period of rapid transmission. In recent years, the number of new HIV infections in my country has increased year by year, with hundreds of thousands of new infections each year (2018, China AIDS Academic Conference). These data have given us a wake-up call. If we do not find a cure for AIDS as soon as possible, HIV will infect more people in our country. It will bring pain to more families and cause greater losses to the national economy. my country’s 90-90-90 target has not yet been achieved; by 2020, it is only possible to achieve 90% of people receiving cART treatment to inhibit the HIV virus in the body; and the other two 90-90 targets may be difficult to achieve because of how certain my country is. Of HIV-infected people do not know that there are hundreds of thousands of new infections every year. The form of the AIDS epidemic in my country is still severe.

HIV-1 is a virus belonging to the genus Lentivirus in the retroviral family. The genome of HIV-1 is approximately 9.8 kb (Figure 1. HIV-1HXB2 genome structure diagram). There are LTR (Long Terminal Repeat) regions at both ends. The main structural proteins of HIV-1 include capsid Gag, enzyme Pol, and membrane protein Env. The Gag protein has a full length of 55KD, including matrix protein region p17 (Matrix, MA), capsid protein p24 (Capsid, CA), nucleocapsid protein (Nucleocapsid, NC) and p6. Pol is responsible for encoding viral protease, integrase and reverse transcriptase. Env is responsible for encoding the membrane proteins Gp120 and Gp41. HIV-1 also encodes some regulatory proteins, such as Vif, Vpu, Vpr, Tat, Rev and Nef. Vif protein antagonizes the antiviral effect of the antiviral protein cytosine deaminase (APOBEC3G) produced by the human body. Vpu antagonizes the adhesion of Tetherin, another antiviral protein produced by the human body. Vpr induces the arrest of G2/M phase of the infected cell cycle and promotes the apoptosis of infected cells. Tat transactivates HIV-1 transcription by binding to the Tar structure of HIV-1 LTR region. Rev is responsible for combining with the HIV-1 Rev response element RRE (Rev Respond Element) to transfer the HIV-1 genome from the nucleus to the cytoplasm for protein translation and virus packaging. Nef protein can down-regulate CD4 and enhance virus replication and infectivity.

Currently, there are anti-HIV-1 drugs including anti-reverse transcriptase inhibitors, proteases, integrases and virus entry inhibitors. Antireverse transcriptase drugs are the earliest drugs developed, such as azidothymidine (AZT), efavirenz (EFV), lamivudine (3TC); protease inhibitors, such as Saquinavir; integration Enzyme inhibitors, such as Raltegravir; virus entry inhibitors, such as Maraviroc. Single use of these drugs can easily induce resistance, and multiple drugs are often used in combination. The commonly used combined antiviral therapy (cART) is two reverse enzyme inhibitors plus one protease inhibitor, such as efavirenz + lamivudine + stavudine (EFV + 3TC + D4T).

The realization of the goal of controlling AIDS globally and in our country lies in finding a cure and an effective vaccine. An effective vaccine is a very difficult goal to achieve. It cannot cover the many subtypes and mutations of HIV. The cure of AIDS is a possible goal after hard work. The existing cART therapy cannot completely cure AIDS and requires long-term life-long treatment; if the drug is stopped, the virus will rebound. The reason why AIDS cannot be cured is the latent reservoir of HIV. The HIV latent pool is formed within 2 to 3 days of virus infection, less than a week, even when the virus has not been detected in the plasma and lymph nodes. Long-term research results show that quiescent long-term CD4memory T cel1 (quiescent long-term CD4memory T cel1) is the main latent reservoir of HIV ^[3-5] .

For the cure of AIDS, people have made a lot of efforts and attempts in the past 30 years. The first is to use a wider variety of drug combinations. In addition to reverse transcriptase inhibitors and protease inhibitors, in August 2007, the U.S. Food and Drug Administration (FDA) approved the HIV co-receptor CCR5 blocker Maraviroc (Maraviroc); in October 2007, The US FDA also approved the integrase inhibitor Raltegravir (Raltegravir) (http://www.fda.gov). The use of integrase inhibitors and CCR5 blockers has increased people's choice of drugs for treatment; if reverse transcriptase inhibitor drugs become resistant, there are more options. However, these applications have not changed the reality of virus rebound after drug withdrawal.

The second attempt is early treatment ^[6-8] . Internationally, for the treatment of AIDS, in the 1990s, due to lack of drugs, in order to avoid side effects and drug resistance, the principle of treatment for AIDS was that CD4 ⁺ cells <200 cells/μl, and patients were started to receive cART treatment. Later, due to the increase of drugs and the reduction of side effects, the World Health Organization (WHO) revised the guidelines, and patients infected with HIV and CD4 ⁺ cells <350 cells/μl were given treatment (http://www.who.int) . In 2011, the results of the international HPTN052 (The HIV Prevention Trials Network) experiment showed that early treatment of HIV-infected people has a significant effect on reducing the spread of HIV ^[9] . Based on this result, a "Treatment as Prevention" program was proposed, so the current treatment principle tends to "discovery is treatment." Although this method may increase the chance of drug resistance ^[10] , it can at least reduce the spread of HIV. However, the early treatment of HIV-infected people has not changed the reality that AIDS cannot be cured. Monkeys who received early drug treatment still showed a viral rebound ^[11,12] .

The third attempt is to target the latent virus library, using the "shock and kill" method internationally. Use an activator to activate the virus in a resting and latent state, make it reproduce, and then kill it with drugs or other methods ^[13] . The activators currently in use include protease C (PKC) antagonists, which are used to activate T cells; and histone deacetylase (HDAC inhibitors), which are used to activate latent viruses ^[5] . The question is, how to kill the virus after it is activated? Drug therapy only inhibits the reproduction of viruses. Can virus-producing cells be killed by human cytotoxic T cells (CTL cells) and natural killer cells (NK cells) ^[14] ? If there is a mutation of the HIV virus, it can still escape the attack of CTL cells and NK cells ^[14] . The activated virus can still generate a new latent library of viruses. This "activation and killing" method needs more evidence to prove its effectiveness?

The fourth attempt was to find the surface markers of the latent library of CD4 cells. PD-1 ⁺ CXCR5 ⁺ CD4 ⁺ cells in the blood and lymph nodes can produce HIV virus ^[15] , but these cells may not be latent cells. There is evidence that CD32a may be a surface marker of CD4 cells in the virus latent library ^[16] , but this result has not been repeated by other laboratories, and even the opposite result has been obtained ^[17] .

Fifth, broadly neutralizing antibody (bNAb). The broad-spectrum neutralizing antibody represented by the US VRC01 can neutralize 98% of the virus. Later, many broad-spectrum neutralizing antibodies have been isolated, such as b12, B3NC117, PG16, 10E8, etc. These broad-spectrum neutralizing antibodies show very good application prospects. However, currently broad-spectrum neutralizing antibodies cannot be successfully induced in vivo. The use of passive immunization, direct injection of bNAb antibody, and the combined application of several antibodies have shown good results. After cART treatment is stopped, the rebound of the virus can be significantly delayed ^[18-20] . However, passive immunization with bNAb can only neutralize free viruses, and it is still impossible to eliminate viruses that are latent in CD4 ⁺ cells. Moreover, long-term injection of broad-spectrum neutralizing antibodies is not a good thing for the human body.

Sixth, bone marrow transplantation. Currently, the only AIDS patient in the world who is cured is "Berlin patient" Timothy Ray Brown. After he suffered from leukemia and AIDS, the doctor performed a bone marrow transplant for him. The donor of the bone marrow was homozygous for CCR5Δ32 deletion ^[21] . After he received a bone marrow transplant, he stopped antiviral treatment. It has been ten years and he still has no symptoms. This is the only cured HIV-infected person in the world. Someone tried to repeat but failed, either due to the viral rebound of CXCR4 tropism, or died of a concurrent tumor. Moreover, at a time when the condition can be well controlled by cART therapy, it is unrealistic to perform bone marrow transplantation for every HIV-infected person.

In fact, we have successfully induced CCR5Δ32 homozygous deletion using gene editing technology CRISPR-Cas9 ^[22] . This method can successfully induce the patient’s cells into CCR5Δ32 homozygous deletion in vitro, and then return it to the patient, which is expected to treat AIDS. people.

Through the above analysis, I have made some elaboration on the latest AIDS progress in the world. I have proposed a brand new idea, which has not been reported in the world, which can clear the latent pool of the virus, that is, use "temporary depletion of CD4 ⁺ cells""Methods.

Summary of the invention

The main objective of the present invention is to eliminate the latent reservoir of HIV and strive to achieve the purpose of curing AIDS. HIV is latent in the human genome. Without replication, it does not express HIV antigens, just like normal cells.

The present invention boldly adopts the method of "temporary depletion of CD4 ⁺ cells", that is, to temporarily eliminate all CD4 ⁺ cells. Instead of using the "shock and kill" method, it is better to temporarily remove all CD4 ⁺ cells, including CD4 ⁺ CCR5 ⁺ and CD4 ⁺ CXCR4 ⁺ cells.

The steps of the method for curing AIDS or HIV infection provided by the present invention are:

(1) Use the currently commonly used combined antiretroviral therapy (cART), that is, two reverse enzyme inhibitors, plus one protease inhibitor, such as lamivudine + efavirenz + stavudine (EFV+ 3TC+D4T), or other combinations, reduce the viral load in the patient's plasma to zero;

(2) then a "transient depletion of CD4 ⁺ cells", regardless of the CD4 ⁺ cell is infected with HIV, all specifically, temporarily remove CD4 ⁺ cells, the main purpose for the removal of latent HIV library that CD4 ⁺ cells drops to zero , The time is as short as possible;

(3) Then, stop the treatment of clearing CD4 ⁺ cells; during this period, continue to combine antiviral cART therapy; wait for CD4 ⁺ cells to slowly return to normal, it takes several weeks to continue antiviral cART therapy;

(4) After waiting for the CD4 ⁺ cells to return to normal and stable, the combined antiviral cART therapy can be stopped to observe whether the virus rebounds; if the HIV virus does not rebound, then AIDS is cured.

The method of "temporarily depleting CD4 ⁺ cells" of the present invention can use anti-human CD4 monoclonal antibodies, polyclonal antibodies, small molecule drugs, polypeptide drugs, lentivirus packaging systems, adenovirus vector systems, and the like.

The advantages of the therapy of the invention are:

It can clear the resting CD4 ⁺ cells-HIV latent pool, which not only clears peripheral blood, but also non-replicating viruses in tissues and lymph nodes, which is expected to cure AIDS. Although it damages normal CD4 ⁺ cells, it is only temporary, transient and tolerable. At the same time, we monitor the size of the HIV latent pool. If the HIV latent pool becomes smaller than before treatment, this method is effective. We can carry out the second CD4 ⁺ elimination treatment, or without stopping the antiviral cART treatment, we can directly carry out the second CD4 ⁺ elimination treatment, and only consider stopping the treatment when the HIV reservoir drops to zero. As long as the virus reservoir is reduced by 10,000 times (4 Log), it is possible to cure AIDS. This therapy was first thought of by the inventor, and it has not been reported in the world, so it applied for patent protection.

In the HIV latent pool, about 93% of the proviruses are defective and cannot replicate, and only the remaining 7% of the viruses can replicate ^[5] . Therefore, internationally, there are methods to identify latent libraries with replication capabilities and latent libraries with defective replication ^[25] . In fact, replication-competent viruses may save these defective viruses when they re-enter the defective CD4 ⁺ cells when they replicate. Therefore, 93% of defective HIV latent libraries that cannot replicate are likely to be reactivated to produce new viruses, and we cannot ignore these libraries. Our method "temporarily depletes CD4 ⁺ cells" can clear these reservoirs together.

The only cured AIDS patient in the world, "Berlin patient", used CCR5Δ32 homozygous bone marrow transplantation ^[21] . The main points of success are (1) the use of immunosuppressive drugs to clear myeloid before transplantation, including cyclosporine and antithymosin; (2) transplantation of CCRΔ32 homozygous bone marrow, anti-CCR5-tropic HIV infection. The "Berlin patient" has stopped taking medication for ten years and is still alive and healthy. The Berlin patient is a special case. It benefits from immunosuppression before transplantation, which inhibits the proliferation of T cells, prevents more T cells from being infected by HIV, and the bone marrow stem cells homozygous for CCR5Δ32 against the HIV CCR5 virus.

The method of the present invention can remove CD4 ⁺ cells temporarily, can clear the latent pool of HIV, prevent more CD4 ⁺ cells from being infected, and has better specificity than myeloablization.

In 2018, the U.S. FDA approved an anti-HIV drug, Ibalizumab, which is also an anti-CD4 monoclonal antibody, but this monoclonal antibody only binds to CD4 and does not cause the reduction of CD4 ⁺ cells, but only prevents the binding of HIV and CD4 receptors ^{[ 26,} ^27] , which is completely different from the anti-CD4 for the purpose of curing in this study. Ibalizumab also cannot cure AIDS, but is just another supplement to existing drugs. Internationally, other methods to deplete CD4 ⁺ cells are to observe the function of CD4 cells ^[28 , ^29] , which is different from the present invention.

The present invention uses the method of "temporary depletion of CD4 ⁺ cells" to clear the latent pool of HIV, combined with the existing antiviral cART therapy, and provides a method for curing AIDS and HIV infection.

Description of the drawings

Figure 1 is a genome structure diagram of the standard HIV-1 strain HXB2 (downloaded from www.hiv.lanl.gov).

Figure 2 is a graph showing changes before and after CD4 cell removal.

detailed description

A method of curing AIDS or HIV infection, the steps of the method are:

(1) Use the currently commonly used combined antiviral therapy (cART), that is, two reversal enzyme inhibitors and one protease inhibitor, such as lamivudine + efavirenz + stavudine (EFV+3TC+ D4T), or other combinations, reduce the viral load in the patient's plasma to zero;

During the experiment, detect the size of the HIV virus pool of CD4 ⁺ cells, and as long as it is reduced by 10,000 times (4 Log), AIDS can be cured. Even if it is reduced by a factor of 100 (2 Log), the second or even the third "temporary depletion of CD4 ⁺ cells" therapy can be performed. In the middle, the patient's CD4 ⁺ cells need to return to normal.

The above method is only "temporary depletion of CD4 ⁺ cells" and has no effect on the lymphatic stem cells that produce CD4 ⁺ cells, and can regenerate new CD4 ⁺ cells without HIV infection. The key to the success or failure of the above method is whether it can clean the free virus first, and then whether it can clean the CD4 ⁺ cells. Because the regenerated CD4 ⁺ cells are not infected with HIV, they are still sensitive to HIV. Therefore, the combined anti-viral cART therapy must be performed before and after the CD4 ⁺ cells are cleaned to ensure that the virus is suppressed and eliminated as much as possible. Eliminating CD4 ⁺ cells is to eliminate the source of HIV production and eliminate the "fortress" of HIV production, so that no new virus will be produced. CD4 ⁺ cells are not only T cells, but also mononuclear macrophages, some dendritic cells, etc., that is, all cells with the CD4 mark. Not only does it remove CD4 ⁺ cells in the peripheral blood, but the antibodies circulate through the blood and lymph to reach various organs and tissues of the human body, including lymph nodes, intestinal tissues, bone marrow, etc. The temporary and specific removal of CD4 ⁺ cells is already the conceivable removal of HIV latent pools in the present invention, which has minimal damage to the human body. Because it targets human CD4 ⁺ cells, not viruses, there will be no drug resistance issues.

The biggest problem that may be encountered is the temporary suppression of the immune function of the human body after the temporary removal of CD4 ⁺ cells, and the possible infection. We are gratified to see that this anti-CD4 monoclonal antibody (English name: Zanolimumab) has been used clinically and has achieved phase II clinical trials. Their purpose is not to treat AIDS, but to treat T-cell lymphoma ^[23,24] . The drug is safe, toxic and side effects can be tolerated, and has a certain effect on the treatment of T-cell lymphoma ^{[23, 24]} . The drug Zanolimumab can be used in the "temporary depletion of CD4 ⁺ cells" of the present invention. In addition, because we are prepared for "transient removal of CD4 ⁺ cells", we can make some preparations before starting, such as using antibiotics for anti-infective treatment, keeping the patient in good condition, and then starting the treatment of removing CD4 ⁺ cells. During the treatment, it can be carried out in a clean sterile environment to observe whether there is cytomegalovirus (CMV) or Epstein-Barr virus infection, and give timely treatment.

The second question, after clearing CD4 ⁺ cells, CD4 ⁺ cells in the human body is able to return to normal? The above-mentioned human experiments have confirmed that after removing CD4 ⁺ cells, human CD4 ⁺ cells can return to normal (Figure 2). Because the stem cells that produce CD4 ⁺ cells are not damaged. Another piece of evidence is that in patients with advanced AIDS, CD4 ⁺ cells have reached zero. After antiviral cART treatment, they can all return to normal, so it is not a problem.

The third question is, after using anti-CD4 antibody, CD4 ⁺ cannot be cleared to zero, and there are residual CD4 ⁺ cells. What should I do? In the above-mentioned Phase II clinical trials, there were indeed some patients whose CD4 ^{+ was} not cleared to zero. At present, we do not expect that this method can cure all HIV/AIDS patients in the world. Even if only 30% are cured, about 10 million people are cured, which is a huge contribution to the world. Assuming that only dozens of people are cured, it is a great encouragement to the world! If the patient can tolerate it, consider whether the current 980mg dose can be increased to eliminate more CD4 ⁺ cells.

The fourth question is, after using anti-CD4 antibodies, will it induce anti-autoantibodies? Anti-CD4 antibodies are auto-antibodies themselves. If they are induced, they will not respond to human CD4 cells. In the aforementioned human experiments, no autoantibodies were found.

The fifth question is that after HIV infects the human body, an accessory protein Nef is produced. Nef has the effect of down-regulating molecules such as CD4 and MHC. When we clean up CD4 ⁺ cells, we may miss HIV-infected CD4 ^- cells. The solution of this problem depends on antiviral cART therapy. Because the production of Nef requires viral replication, antiviral therapy, the use of reverse transcriptase inhibitors, protease inhibitors, and integrase inhibitors can inhibit HIV replication and inhibit the production of Nef protein. Therefore, the antiviral cART therapy must be used in the early stage of the therapy to inhibit the replication of HIV virus as much as possible and clean up the free virus as much as possible. "Transient depletion of CD4 ⁺ cells" is not suitable for people with advanced AIDS, because their CD4 ^{+ is} already very low. If it is used, it will worsen the condition, and it will make the situation worse. It must be considered after antiviral treatment first.

The sixth problem is that after the CD4 cells are cleared, the immune memory of CD4 T cells may be lost, that is, the vaccine that has been injected before is no longer useful. If this is the case, for such a person, when the body returns to normal, the vaccine can be supplemented to re-stimulate the immune response.

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Claims

A method of curing AIDS or HIV infection, specifically using the method of "temporary depletion of CD4 + cells" to temporarily remove all CD4 + cells in the human body and clear the latent reservoir (repository) of HIV; the implementation steps are:

(1) Using the currently commonly used combined antiretroviral therapy (cART), that is, two reverse enzyme inhibitors and one protease inhibitor, so that the viral load in the patient's plasma is reduced to zero;

(2) Then adopt the "temporary depletion of CD4 + cells", regardless of whether the CD4 cells are infected with HIV or not, the CD4 + positive cells will be specifically and temporarily removed. The main purpose is to clear the latent pool of HIV and reduce the CD4 + cells to zero ；

(3) Stop the treatment of clearing CD4 + cells; during this period, continue to combine antiviral cART therapy; wait for CD4 + cells to slowly return to normal, continue to combine antiviral cART therapy;

(4) After waiting for the CD4 + cells to return to normal and stable, stop the combined antiviral cART treatment and observe whether the virus rebounds; if the HIV virus does not rebound, then AIDS is cured.
The method for curing AIDS or HIV infection according to claim 1, wherein the method of "temporarily depleting CD4 + cells" uses anti-human CD4 monoclonal antibodies or polyclonal antibodies.
The method for curing AIDS or HIV infection according to claim 1, wherein the method of "temporarily depleting CD4 + cells" uses small molecule drugs.
The method for curing AIDS or HIV infection according to claim 1, wherein the method of "temporarily depleting CD4 + cells" uses polypeptide drugs.
The method for curing AIDS or HIV infection according to claim 1, wherein the method of "temporarily depleting CD4 + cells" adopts viral therapy.
The method for curing AIDS or HIV infection according to claim 5, wherein the virus therapy is a lentivirus packaging system or an adenovirus vector.