Can AIDS be cured?

Abstract: Bone marrow transplantation containing the CCR5 mutation gene may be suitable for the treatment of patients of different races and genders who suffer from AIDS and blood cancer at the same time

AIDS, or Acquired Immune Deficiency Syndrome (AIDS), is caused by the Human Immunodeficiency Virus (HIV), also known as HIV

HIV belongs to the human lentivirus group in the genus Lentiviridae of the family Viridae.

Figure 1.

Like all viruses, HIV replicates the virus using the genetic machinery (replicon) of the host cell, usually the CD4 lymphocyte (as shown in Figure 2)

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Drugs used to treat HIV infection are developed based on the HIV life cycle

Figure 2.

Three AIDS cure "lucky people", is it accidental or inevitable

1

The first case--Berlin patient

In November 2008, the world's first cured case of AIDS was reported

Figure 3.
Research results (Source: NEJM)

The world's first AIDS cure is named Timothy Ray Brown (hereinafter referred to as "Brown"), also known as the "Berlin Patient"
.
In fact, Brown was born in the United States in 1966 and is called the "Berlin Patient" because he was diagnosed with HIV in 1995 while living in Berlin, Germany
.
Brown developed acute myeloid leukemia (a type of blood cancer) in 2007, for which he underwent a bone marrow transplant
.

Brown's attending physician, Gero Hutter, is a hematologist but not an AIDS specialist, but when he realized Brown needed a bone marrow transplant, he remembered a paper he had read more than 10 years ago about some people with Special genetic variants that make them resistant to AIDS
.
The variant refers to the deletion of a small segment of the CCR5 gene, which encodes a receptor that HIV uses to invade immune cells called CD4+ T cells
.
About 1% of the European population has a 2-copy variant of the CCR5 gene, which makes it difficult for these people to become infected with HIV
.
If Hutter could replace a patient's immune cells with the cells lacking the CCR5 receptor, the patient might be less susceptible to HIV infection
.
Based on this, Hutter found 80 suitable matches for this patient at the German Bone Marrow Donation Center, of which bone marrow donor No.
61 was confirmed to have this CCR5 mutation
.

In February 2007, Hutter performed the transplant on the patient
.
Shortly after the operation, the CCR5Δ32/Δ32 mutation was detected in Brown's somatic cells, and the virus content in the blood was also greatly reduced, but it didn't take long for the leukemia to recur again.
Brown received hematopoietic stem cell transplantation from the same donor again.
Gero Hütter added Increase the intensity of myeloablation, trying to eliminate all cancer cells
.
After the second bone marrow transplant, Brown went through a terrifying dungeon, but eventually not only was the leukemia cured, but his HIV virus dropped to undetectable levels
.

After 12 years, Brown relapsed with leukemia in 2019 and died in 2020
.

The "Berlin Patient" seemed to be a "small probability event" at the time, and Dr.
Hutter was the key
.
The CCR5 mutation, which plays a decisive role, is carried by about 1% in Europeans, and seldom in Africans, Asians and South Americans.
The proportion of Chinese Han people is only 0.
16%, and that of Uyghur people is as high as 3%.
%
.

2

Counter-evidence--Boston Patient

The "Boston Patients" were two people who had both HIV and lymphoma
.
The Timothy Henrich treatment team at Brigham and Women's Hospital in Boston performed bone marrow transplants in 2008 and 2010, respectively
.
However, the donor who provided them with bone marrow was only the right type and did not possess the CCR5Δ32 mutant gene
.

Eight months after the surgery, the HIV in the two disappeared
.
In 2013, Henrich's team announced at the International AIDS Society meeting in Kuala Lumpur, Malaysia that they had functionally cured two AIDS patients, marked by undetectable HIV in their blood a few weeks after stopping antiretroviral drugs.

.

However, after Henrich's team returned to China, they found that HIV was detected in a "Boston patient" who stopped taking the drug for 12 weeks, and another "Boston patient" also found that HIV had "returned" after stopping the drug for 32 weeks
.
In this regard, Henrich and other professionals speculate that because the transplanted donor bone marrow does not have the CCR5Δ32 mutation gene, it cannot resist HIV.
Once the drug is stopped for a long time, the HIV hidden in the patient's body will resurface
.

3

The second case--London patient

In 2020, Gupta et al.
published a paper in Lancet (shown in Figure 4), reporting on the study of curing AIDS patients through bone marrow transplantation
.
This is an unnamed British male patient, known as the "London Patient", who has volunteered for transplants for people with HIV and blood cancers
.

Figure 4.
Research results (Source: Lancet)

In 2003, the "London patient" was infected with HIV; in 2012, he began to receive antiretroviral drug treatment, and was diagnosed with Hodgkin's lymphoma in the same year; in 2016, the treatment team searched for a bone marrow transplant match for him for a bone marrow transplant operation.
The donor carried two Mutated CCR5Δ32 allele, mainly for the treatment of hematological malignancies; in March 2019, 16 months after bone marrow transplant, no HIV was detected in the "London patient", who subsequently voluntarily suspended antiretroviral drug therapy
.
Thirty-five months after transplantation, the leukocytes of the "London patient" could not be infected by the CCR5-dependent strain of HIV, and the HIV-1 viral load in the plasma was consistently below the detection limit to be undetectable
.

Ravindra Kumar Gupta, a professor at Cambridge University, who led the study, said: "This result means that the 'London patient' is the second AIDS patient to be cured so far, and it also shows that in 'Berlin' The effects of a stem cell transplant "obtained in a patient can be reproduced in another patient
.
" However, Gupta cautioned that such therapies are high-risk and should only be used as a last resort for those who also suffer from hematologic conditions.
The disease of AIDS patients does not apply to all patients
.

4

The third case - New York patient

Yvonne Bryson, MD, researcher, director of pediatric infectious diseases at UCLA, speaks at the 2022 Conference on Retroviruses and Opportunistic Infections (CROI) on February 15, 2022, of a person living with HIV from a multiracial background Healed by cord blood stem cell transplantation
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In order to protect personal privacy, the patient refused to disclose the race and age of the individual
.
It is reported that the patient is a middle-aged New York mixed-race woman who was diagnosed with early HIV infection in 2013, followed by rapid treatment, and reached a level of undetectable viral load
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In 2017, the woman was diagnosed with leukemia and received a transplant of cord blood from an umbilical bank, which carries a mutation in the CCR5 gene that makes the immune system resistant to HIV
.

After the patient's transplant, the HIV viral load decreased to undetectable levels and has continued to do so until now
.
Meanwhile, after the transplant, her immune system began to rebuild itself using the transplanted HIV-resistant cells
.

The three "lucky people" differ in that: the "Berlin Patient" is Caucasian, the "London Patient" is Latino, and the "New York Patient" is multiracial, the former two received a bone marrow transplant and the latter received a Umbilical cord blood transplant; in common: had both AIDS and blood cancer and received a transplant containing the CCR5 mutation
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Combined with the contradictory evidence of the "Boston Patient", it shows that bone marrow transplantation containing the CCR5 mutation gene may be suitable for the treatment of patients of different races, different genders, and suffering from AIDS and blood cancer at the same time
.
While these cases provide proof of concept that HIV can be cured, they are not a viable large-scale strategy to cure HIV
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The number of HIV infections hits a new high, and the number of new HIV infections in China exceeds the global average

HIV-1 originated in central Africa and first emerged in the first half of the 20th century when a closely related chimpanzee virus infected humans
.
The HIV-1 virus began to spread globally in the late 1970s, and by 1981, AIDS was first recognized in humans
.

The latest report released by UNAIDS (shown in Figure 5) shows that since the beginning of the AIDS epidemic, 79.
3 million people have been infected and 36.
3 million people have died
.
As of June 30, 2021, there were 37.
7 million people living with HIV worldwide
.
In 2020, there will be 1.
5 million new HIV infections, 28.
2 million people receiving antiretroviral therapy, and 680,000 deaths
.
The majority (86%) of new infections occurred in developing countries; more than half occurred in women in sub-Saharan Africa
.
In many sub-Saharan African countries, however, the number of new HIV infections has fallen sharply, in part due to the international community's provision of treatments and strategies for prevention
.

Figure 5.
About 38 million people living with HIV worldwide (Source: UNAIDS official website)

According to the data of the Chinese Center for Disease Control and Prevention (as shown in Figure 6), by the end of 2020, there are about 1 million people living with HIV in China, and the annual incidence rate is on the rise
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From January to October 2019, a total of 230 million people were tested nationwide, and new reports found 131,000 infected people; as of the end of October 2019, China reported 958,000 surviving infections
.
Judging from the annual new case data from the National Bureau of Statistics, there were 71,200 new AIDS cases in China in 2019, a year-on-year increase of 10.
96%
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Both existing HIV infections and new AIDS cases in China are on the rise, and the growth rate exceeds the global average
.

Figure 6.
Statistics on the number of new AIDS cases and deaths in China from 2010 to August 2020

(Data source: Chinese Center for Disease Control and Prevention | Graphics: Bio-Exploration Editorial Team)

Complex HIV, difficult vaccine development

2021 marks the 40th anniversary of the first reported AIDS case in humans, but there is no specific treatment for HIV.
The drugs used to treat HIV infection can only control the replication of the virus and cannot completely remove the virus
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Therefore, the development of safe and effective vaccines is one of the important means to control the spread of HIV
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HIV-susceptible people can develop immune response by vaccinating against AIDS, thereby generating specific resistance to the disease, improving the immune level, and achieving the purpose of preventing and treating HIV
.

Since 1983, the research and development of HIV vaccines has been uninterrupted, but there are no approved vaccines on the market
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Why is developing an HIV vaccine so difficult? This is attributed to the HIV virus mutating, stealth and evading immune control
.

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The protein on the surface of HIV is coated with a layer of sugar molecules, which is like wearing a coat, making it difficult for the immune system to recognize HIV and thus unable to produce antibodies to fight infection;

As a retrovirus, the reverse transcriptase of HIV is very error-prone, resulting in an extremely fast mutation rate, and the human immune system cannot keep up.
More flu virus mutations accumulate during the flu season;

HIV is divided into two main types, and there are multiple subtypes under each type, and different subtypes are constantly re-formed into new subtypes during the epidemic;

Lack of suitable animal models for vaccine development;

There is a lack of funding for vaccine development
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Funding for AIDS vaccine development has declined since 2010, with 85 percent of funding provided by the U.
S.
government and the Bill & Melinda Gates Foundation
.
In 2018, the total contribution of the two was about $680 million
.

Therefore, said Laufer, vice-president of the International AIDS Vaccine Initiative (IAVI): "The challenge that HIV presents to vaccine development is that it is almost not one virus, but millions of different viruses
.
"

For the above reasons, although preclinical and clinical researches on HIV vaccines with different technical routes have been carried out since the end of the last century (as shown in Table 1 and Table 2), there are viral vector vaccines (adenovirus, poxvirus), and there are There are also DNA nucleic acid vaccines and protein subunit vaccines, but four or five of them failed early, and there were only a handful of studies left, which lasted for nearly two years, and ended in embarrassment as well
.

Table 1.
Main types of HIV vaccines

Data source: [3]｜Table: Biodiscovery editorial team

Table 2.
Recent HIV vaccine clinical trials

Data source: [4]｜Table: Biodiscovery editorial team

Is the development of HIV vaccine helpless? Whether a vaccine can be produced to provide immunity against this virus
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The results of the RV144 trial, obtained in 2009, were a major breakthrough, showing that a preventive HIV-1 vaccine is possible
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The experimental results showed that the vaccine efficacy of the RV144 trial was 60% at 12 months and 31% at 3.
5 years
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Based on the results of the RV144 trial, the scientists conducted a similar trial in South Africa, HVTN702
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This vaccine regimen is designed to improve the efficacy and duration of immune response of RV144
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Modifications of RV144 include changing the clades present in the vaccine due to regional differences, changing the adjuvant in the protein boost from alum to MF49, and changing the timing of vaccination from four injections over a six-month period to an injection over a twelve-month period Five times
.
However, HVTN702 was terminated early because an independent data and safety monitoring committee found the vaccine to be ineffective, and participants who received the vaccine had roughly the same number of HIV infections as those who received a placebo
.

Conclusion: To address HIV vaccine development, more research, funding, and clinical trials are needed
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Researchers have been developing vaccines for 30 years, and gene therapy applications of chimeric antigens, broadly neutralizing antibodies and induction of broadly neutralizing antibodies have shown significant progress and may provide us with an HIV-1 vaccine in the future
.
Let us all look forward to the day when the AIDS vaccine will enter every household
.

References:

[1]Hütter G, Nowak D, Mossner M, et al.
Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation.
N Engl J Med.
2009 Feb 12;360(7):692-8.
doi : 10.
1056/NEJMoa0802905.
PMID: 19213682.

[2] Gupta RK, Peppa D, Hill AL, et al.
Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report.
Lancet HIV.
2020 May;7( 5): e340-e347.
doi: 10.
1016/S2352-3018(20)30069-2.
Epub 2020 Mar 10.
PMID: 32169158; PMCID: PMC7606918.

[3] Li Wei, Xu Jing.
Research progress of AIDS vaccine [J].
Chinese Journal of Microbiology and Immunology, 2020, 40(07): 563-568.

[4] Hargrave A, Mustafa AS, Asma H, et al.
Current Status of HIV-1 Vaccines.
Vaccines (Basel).
2021 Sep 16;9(9):1026.
doi: 10.
3390/vaccines9091026.
PMID: 34579263; PMCID : PMC8471857.

[5] Zhang P, Narayanan E, Liu Q, et al.
A multiclade env-gag VLP mRNA vaccine elicits tier-2 HIV-1-neutralizing antibodies and reduces the risk of heterologous SHIV infection in macaques.
Nat Med.
2021 Dec; 27(12):2234-2245.
doi: 10.
1038/s41591-021-01574-5.
Epub 2021 Dec 9.
PMID: 34887575.