The most effective “cocktail therapy” for HIV treatment can effectively control the replication of the virus in the body.
HIV-infected patients with less than 50 copies of RNA per milliliter of blood can expect to live 30-40 years or more. However, because the virus cannot be cleared, long-term medication is required, which causes a lot of inconvenience to the infected individual. Therefore, new therapies are needed to achieve a “functional cure” for HIV, a state of sustained remission after treatment, where HIV RNA per milliliter of blood is maintained even after discontinuation of antiviral drugs.
RNA remains below 50 copies per milliliter of blood, and T-cell numbers and function remain normal.
The Berlin patient is the only AIDS patient recognized to have been completely cured through a blood stem cell transplant (commonly known as a bone marrow transplant). American Brown, an AIDS patient living in Berlin, Germany, who had been on highly active combination antiretroviral therapy (commonly known as “cocktail” therapy) since 1996, was found to have leukemia in 2006 and was dying. After chemotherapy, he received a CCR5 receptor Δ32 pureton mutation hematopoietic stem cell transplant and stopped his antiretroviral treatment in 2008. To date, not only has Brown’s leukemia not returned, but HIV is undetectable in his body and he has been miraculously “cured” of AIDS.
The HIV in Brown’s body was “cleared” thanks to a stem cell transplant with the CCR5 gene defect. The implanted stem cells survived and differentiated in Brown’s body, replacing Brown’s own blood cells, so that Brown’s new CD4 cells not only had normal immune function, but also resisted HIV-1 infection because the cell surface lacked CCR5, a co-receptor necessary for HIV invasion.
However, Brown’s luck is difficult to replicate because the stem cells used for transplantation require not only a successful tissue match, but also a pure mutation in the CCR5 gene. With a tissue match rate of 1 in 400-10,000 for non-blood related humans, a successful match is difficult enough, and since no Chinese population has been found to carry the CCR5 pure gene mutation, it is almost impossible to find a suitable donor, making this method difficult to replicate in the population.
Attempt to mimic, slightly lose details – Boston patient Researchers at Brigham and Women’s Hospital in Boston, USA, attempted to replicate the Berlin patient. 2 AIDS patients also received blood stem cell transplants, which differed from the Berlin patient in that these stem cells carried the normal CCR5 gene. After transplantation, the patients’ HIV
RNA remained below 50 copies per mL for a long time after transplantation, CD4 cell counts gradually rebounded, anti-HIV-1 antibody titers and antigen affinity gradually decreased, and viral DNA was less than 0.13 copies per million individual nucleated cells. These signs indicate that HIV-1 replication in the body is effectively suppressed and that the “reservoir capacity” of the viral reservoir is decreasing. However, after 12 and 32 weeks of discontinuation of antiviral therapy, both patients experienced viral rebound. This is further evidence that stem cell donors carrying the CCR5 gene defect are the key to hematopoietic stem cell transplantation for AIDS treatment.
Borrowing from Nature, Bionic Modification – CCR5 Gene Modification Since T cells with the CCR5△32 gene mutation can naturally protect against HIV infection without losing normal immune function, can this change be achieved artificially? Researchers at the University of Pennsylvania used a zinc finger nuclease gene modification to modify HIV patients’ own T cells in a way that mimicked the “Berlin patient” case, and constructed CCR5△32 mutant CD4+ T cells that were then transfused back into the patient.
T cells, which were then infused back into the patient. These T cells are able to survive in the patient’s body and defend against viral infection without the use of drugs. After 1 week of the initial infusion, the percentage of genetically modified T cells in the patient’s body increased rapidly. Although these cells gradually fell back in the blood over the course of several weeks, the decline in the modified cells during the interruption of antiviral therapy was much less than that of the unmodified T cells. The six individuals enrolled in the trial were completely off antiretroviral therapy for up to 12 weeks without viral rebound, starting 4 weeks after importation.CCR5 genetically modified T-cell transplants are relatively safe, but have the disadvantage that the cells have a limited lifespan, necessitating repeated transplants and increasing risk and cost.
Early treatment, no time to lose – a “functional cure” for AIDS In March 2013, researchers at the 20th Conference on Retroviruses and Opportunistic Infections reported the world’s first “functional cure” for AIDS –The “Mississippi baby,” an HIV-infected infant born with antiretroviral therapy started 30 hours after birth, had undetectable HIV at two years of age after treatment interruption. plasma HIV
Although the infant experienced a rebound in plasma HIV RNA and restarted antiretroviral therapy 27 months after discontinuation, the case still suggests to scientists that early antiretroviral therapy can minimize the size of the HIV reservoir, prolong remission from virologic relapse, and slow disease progression. Questions about the optimal timing and duration of initiation of antiviral therapy and methods of viral reservoir evaluation remain to be investigated.
HIV-1-infected patients without combination antiviral therapy usually have difficulty controlling blood levels of the virus, but about 1% of infected patients are able to maintain blood HIV-1 at undetectable levels for a long time in a natural state without treatment. The French VISCONTI study observed that some 15% of those who started antiviral therapy early in HIV-1 infection were still able to control their viremia 24 months after interrupting treatment. These infected individuals did not have the dominant genetic background or cellular immune response that may play a role in naturally controlling viremia in infected individuals, nor were viral load and CD4 cell levels at the time of initial antiviral therapy determinants, presumably reducing the extent of HIV invasion of the immune system and limiting the size of the body’s HIV viral reservoir early in HIV infection with antiviral therapy.
The size of the reservoir determines the time to relapse, and the smaller the reservoir, the later the relapse. The “kill it all” strategy is to activate latent HIV, drive it out of the cells, and then kill the released virus through antiviral therapy or combination immunotherapy, thus reducing the reservoir.
In 2006, a new histone deacetylase inhibitor, vorinostat, was approved by the U.S. FDA for the treatment of cutaneous T-cell lymphoma. Recently, researchers have observed a significant increase in HIV RNA in latently infected CD4+ T cells after a single oral dose of vorinostat in patients undergoing antiviral therapy.
Other studies have also observed that the comparable drugs pabisterostat and romidepsin have a stronger ability to activate viral reservoirs than vorinostat.
Several clinical trials on the use of vorinostat and similar drugs in HIV treatment are currently underway in China and abroad. However, further research is needed regarding the frequency and duration of administration of such drugs, as well as the possible side effects and tolerability of this therapy.
Note: At this time, despite the announcement by Brigham and Women’s Hospital in Boston that two patients suspected of being cured of HIV after bone marrow transplants had relapsed and that the virus in the “Mississippi babies” had rebounded and restarted antiviral therapy, these examples provide scientists with vital clues about HIV control and They show that early and aggressive treatment can dramatically reduce the reservoir of HIV in infants. Currently, the only person with AIDS recognized by the medical community as “cured” is the “Berlin patient” in this article.