Tag: HIV treatment

Categories : Genetics HIVTags :

Curing HIV with a Dual Gene Editing Approach

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Source: Pixabay CC0

Gene editing therapy aimed at two targets – HIV-1 and CCR5, the co-receptor that helps the virus get into cells – can effectively eliminate HIV infection, report scientists in PNAS. This is the first to combine a dual gene-editing strategy with antiretroviral drugs to cure animals of HIV-1.

“The idea to bring together the excision of HIV-1 DNA with inactivation of CCR5 using gene-editing technology builds on observations from reported cures in human HIV patients,” said Kamel Khalili, PhD, professor at the Lewis Katz School of Medicine. “In the few instances of HIV cures in humans, the patients underwent bone marrow transplantation for leukaemia, and the donor cells that were used carried inactivating CCR5 mutations.”

Dr Khalili and Howard E. Gendelman, MD, professor at UNMC, were senior investigators on the new study from the Lewis Katz School of Medicine at Temple University and the University of Nebraska Medical Center (UNMC). The two researchers have been long-time collaborators and have strategically combined their research strengths to find a cure for HIV.

“We are true partners, and what we achieved here is really spectacular,” Dr Gendelman said. “Dr Khalili’s team generated the essential gene-editing constructs, and we then applied those constructs in our LASER-ART mouse model at Nebraska, figuring out when to administer gene-editing therapy and carrying out analyses to maximise HIV-1 excision, CCR5 inactivation, and suppression of viral growth.”

In previous work, Drs Khalili and Gendelman and their respective teams showed that HIV can be edited out from the genomes of live, humanised HIV-infected mice, leading to a cure in some animals. For that research, CRISPR gene-editing technology for targeting HIV-1 was combined with a therapeutic strategy known as long-acting slow-effective release (LASER) antiretroviral therapy (ART). LASER ART holds HIV replication at low levels for long periods of time, decreasing the frequency of ART administration.

Despite being able to eliminate HIV in LASER-ART mice, the researchers found that HIV could eventually re-emerge from tissue reservoirs and cause rebound infection. This effect is similar to rebound infection in human patients who have been taking ART but suddenly stop or experience a disruption in treatment. HIV integrates its DNA into the genome of host cells, it can lie dormant in tissue reservoirs for long periods of time, out of reach of antiretroviral drugs. As a consequence, when ART is stopped, HIV replication renews, giving rise to AIDS.

To prevent rebound infection, Dr Khalili and colleagues began work on next-generation CRISPR technology for HIV excision, developing a new, dual system aimed at permanently eliminating HIV from the animal model. “From success stories of human HIV patients who have undergone bone marrow transplantation for leukaemia and been cured of HIV, our hypothesis was that the loss of the virus’s receptor, CCR5, is important to permanently eliminating HIV infection,” he explained. They developed a simple and more practical procedure for the inactivation of CCR5 that includes an IV inoculation of the CRISPR gene editing molecule.

Experiments in humanized LASER-ART mice carried out by Dr Gendelman’s team showed that the constructs developed at Temple, when administered together, resulted in viral suppression, restoration of human T-cells, and elimination of replicating HIV-1 in 58% of infected animals. The findings support the idea that CCR5 has a key role in facilitating HIV infection.

The Temple team also anticipates soon testing the dual gene-editing strategy in non-human primates.

The new dual CRISPR gene-editing strategy holds exceptional promise for treating HIV in humans. “It is a simple and relatively inexpensive approach,” Dr Khalili noted. “The type of bone marrow transplant that has brought about cures in humans is reserved for patients who also have leukaemia. It requires multiple rounds of radiation and is not applicable in resource-limited regions, where HIV infection tends to be most common.”

Source: Temple University Health System

Categories : HIVTags :

Earlier HIV Diagnosis and Treatment Improves Outcomes

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HIV themed candle
Image by Sergey Mikheev on Unsplash

Compared to delaying antiretroviral treatment (ART) early in the course of HIV infection, an earlier start to ART when the immune system is stronger results in better long-term health outcomes, according to findings presented at the IDWeek Conference.

The findings are based on an extended follow-up of participants in the National Institutes of Health-funded Strategic Timing of Antiretroviral Treatment (START) study. In 2015, START demonstrated a 57% reduced risk of AIDS and serious non-AIDS health outcomes among participants who began ART when their CD4+ T-cell counts were greater than 500 cells/mm³ compared with those who did not begin ART until either their CD4+ counts fell below 350 cells/mm³ or they developed AIDS. Following the 2015 report of these findings, the participants in the deferred treatment arm were advised to begin ART.

The international START study proved the benefit of early ART initiation, but longer-term follow-up of 4446 participants was undertaken to determine whether the health benefits of early ART compared with deferred ART increased, remained constant, or declined after the participants in the deferred arm were advised to begin ART. The primary study endpoints included the number of participants who developed AIDS; those who developed serious non-AIDS health conditions, such as major cardiovascular disease, kidney failure, liver disease and cancer; and those who died.

For participants who began ART before the end of 2015, the median CD4+ cell count at the time of ART initiation was 648 cells/mm³ for the immediate arm and 460 cells/mm³ for the deferred arm. The analysis presented today compared the primary study endpoints before the end of 2015, with those in the extended follow-up period, from 2016–2021. In the latter period, most deferred-arm participants were taking ART. During the second period, people initiating ART in the deferred group had rapid and sustained declines in HIV viral load (less than or equal to 200 copies/mL); however, CD4+ cell counts remained, on average, 155 cells lower compared with that of individuals in the immediate ART group.

While the risk of serious health outcomes was substantially diminished soon after ART was initiated in the deferred treatment group, some excess risk remained compared with the immediate treatment group. The deferred ART group continued to have a somewhat greater risk (21%) of serious health consequences or death in comparison to the immediate treatment group. Over the five-year follow-up, there were 27 cases of AIDS in the deferred group compared with 15 cases in the early group. Similarly, 88 cases of serious non-AIDS health issues occurred in the deferred treatment arm compared with 76 cases in the immediate treatment arm. Lastly, there were 57 deaths in the deferred treatment group compared to 47 in the immediate treatment arm.

These findings confirm that ART significantly improves the health of an individual with HIV and reduce the person’s risk of developing AIDS and serious health issues, and that early diagnosis and treatment are key to maximising these benefits and reducing risk, according to the presenters.

Source: NIH/National Institute of Allergy and Infectious Diseases

Categories : HIVTags :

SA HIV Clinicians Update Dolutegravir Guidelines

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HIV themed candle
Image by Sergey Mikheev on Unsplash

The South African HIV Clinicians Society (SAHCS) have recently announced a clinical update on the dolutegravir (DGT)-based regimens for first- and second-line antiretroviral therapy. This comes in the wake of positive findings from a number of clinical trials.

The clinical guidelines are available for download as a PDF.

“Based on data from several recent trials, we now recommend that all patients > 10 years old and 35 kg on tenofovir/emtricitabine (or lamivudine)/efavirenz (TEE/TLE) or NVP-based regimens be switched to tenofovir/lamivudine/dolutegravir (TLD) regardless of the viral load (VL) result. In addition, all patients > 10 years old and > 35 kg on a regimen of two nucleoside reverse transcriptase inhibitors (NRTI) with a boosted protease inhibitor (PI) (eg, lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r)) and a suppressed VL can be switched to TLD, regardless of prior resistance patterns or treatment history.”

In South Africa, pre-treatment resistance to nonnucleoside reverse transcriptase inhibitors (NNRTI)-based antiretroviral therapy regimens has been rising. Meanwhile, DTG has a higher barrier to resistance and reduced side effects. This prompted the Department of Health to recommend that patients on NNRTI-based ART regimens be switched to DTG-based regimens. This transition is slower than desired partly because a documented suppressed VL is required prior to switching from TEE/TLE to TLD. Since this recommendation was first made, evidence from several trials (NADIA, VISEND and ARTIST) has demonstrated that tenofovir with lamivudine can be safely and effectively recycled from a first- to a second-line regimen. Therefore, the SAHCS has stated that “in patients with virological failure on a TEE or TLE regimen a single drug can be switched (efavirenz to dolutegravir ie, TLD as secondline), resulting in virological suppression comparable to or better than alternative second-line options.”

The guidelines also outline the results of the NADIA, VISEND and ARTIST trials conducted in southern African countries, as well as the single-arm DAWNING trial.

Source: South African HIV Clinicians

Categories : HIVTags :

Scientists Find Second HIV Patient Achieved a ‘Sterilising Cure’

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HIV infecting a human T9 cell. Credit: NIH

In a study published in the Annals of Internal Medicine, scientists have reported the identification of a second HIV patient who appears to have completely eliminated HIV from their systems in a ‘sterilising cure’. 

During infection, HIV creates a viral reservoir by inserting copies of its genome into a cell’s DNA. This allows the virus to escape from anti-HIV drugs and the body’s immune response. In most people, new viral particles are constantly made from this reservoir. Antiretroviral therapy (ART) can prevent new viruses from being made but cannot eliminate the reservoir, necessitating daily treatment to suppress the virus.

Some, known as ‘elite controllers’, have immune systems that are able to suppress HIV without the need for medication. Though they still have viral reservoirs that can produce more HIV virus, a type of immune cell called a killer T cell keeps the virus suppressed without the need for medication.

Xu Yu, MD, a physician investigator at Massachusetts General Hospital, led a research group that identified one patient with no intact HIV viral sequence in her genome, indicating that her immune system may have eliminated the HIV reservoir: a sterilising cure. When they sequenced billions of cells from this patient, known as the San Francisco Patient, searching for any HIV sequence that could be used to create new virus, they found no sign. This extraordinary finding, the first known incidence of a sterilising cure without a stem cell transplant, was reported in Nature in 2020.  

Now, Dr Yu’s group reports a second untreated HIV-infected patient, known as the Esperanza Patient who also has no intact HIV genomes found in more than 1.19 billion blood cells and 500 million tissue cells sequenced. This may represent a second instance of a sterilising cure.

“These findings, especially with the identification of a second case, indicate there may be an actionable path to a sterilizing cure for people who are not able to do this on their own,” said Dr Yu.

She further explains that these findings may suggest a specific killer T cell response common to both patients driving this response, with the possibility that other people with HIV have also achieved a sterilising cure. If researchers can figure out the immune mechanisms behind this response, they could develop treatments that teach others’ immune systems to mimic these responses in cases of HIV infection.  

Yu adds: “We are now looking toward the possibility of inducing this kind of immunity in persons on ART through vaccination, with the goal of educating their immune systems to be able to control the virus without ART.”

Source: EurekAlert!