Researchers has found that duoCAR-T cells they created are effective against HIV


A team of researchers affiliated with several institutions in the U.S., working with biotech firm Lentigen, has found that duoCAR-T cells they created were effective against HIV in human mouse models.

In their paper published in the journal Science Translational Medicine, the group describes how the duoCAR-T cells were created and how well they worked in human mouse models.

Chimeric antigen receptor (CAR)-T cells are T cells that are removed from a patient and genetically altered to give them new properties.

In recent cases, they have been altered in ways that push them to more effectively attack cancer cells.

The technique involves adding a gene for a type of receptor that binds to proteins found only in cancer cells.

Several years ago, a team of researchers tried the technique with HIV patients.

It proved effective under certain circumstances, but the researchers found that the CAR-T cells themselves were easily infected by the virus.

In this new effort, the researchers took an updated approach to using CAR-T cells to combat HIV, doubling up their chimeric antigen receptor molecules.

The resultant cells have been named duoCAR-T cells.

The researchers report that the advantage of the new approach is that instead of altering T cells to use the CD4 receptor as a targeting site, multiple sites on the HIV envelope can be targeted.

The two particular molecules that were used were found by developing over 40 lentiviral vectors and testing them to see which were the most effective.

The researchers report that when tested in the lab, their duoCAR-T cells eliminated approximately 99 percent of 11 strains of infected immune cells.

When tested on human mouse models, doses of duoCAR-T cells were able to suppress HIV infections by 97 percent after just a week of treatment—far better than traditional CAR-T cells.

The team reports also that the duoCAR-T cells proved to be resistant to infection, overcoming the main problem with traditional use of CAR-T cells for treatment of HIV patients.

And finally, they report that clinical trials aimed at testing the effectiveness and safety of the new approach are scheduled to start as early as this spring.

High systemic immune activation has a pivotal role in HIV-1 pathogenesis [1].

Studies have associated the elevated immune activation with CD4+ T cell depletion and progression to AIDS [27].

During primary HIV-1 infection (PHI), viral loads can reach values higher than one million HIV-1 RNA copies/mL, and a significant decrease in CD4+ T cell counts occurs [89].

A high production of pro-inflammatory cytokines, called a “cytokine storm”, arises in response to virus replication [10].

A controlled initial pro-inflammatory immune response may be beneficial, as observed in natural SIV hosts, which displayed significant increases in plasma cytokines and interferon-stimulated gene (ISG) expression, normalized four weeks after infection [11].

However, in the context of HIV-1 infection, the pro-inflammatory response remains elevated after the end of the acute phase, and most individuals without cART develop progressive immune dysregulation, culminating in AIDS [8].

The cART has had an enormous impact on mortality and morbidity in HIV-1 infection [1214]. Studies in the cART era have demonstrated a shift in the causes of death and morbidities in HIV-1-infected individuals, with a proportional increase of non-AIDS-related events, such as cardiovascular, liver, and renal diseases, when compared with AIDS-related events [1520].

Also, a higher prevalence of age-related noninfectious comorbidities was observed in HIV-1-infected individuals than in the general population [21].

Alongside this, a strong association between inflammation and AIDS and non-AIDS-events became evident [2224].

Several biomarkers of inflammation have been associated with disease progression and mortality in HIV-1 infection [25].

Among these markers, IL-6 and CRP were associated with an increased risk of AIDS [23] or death [2224].

IL-6 levels, at time of seroconversion, also predicted HIV-1 disease progression [26]. The markers of monocyte activation sCD14 and sCD163 are associated with a higher risk of death [2729].

And, during the PHI, CRP levels were significantly higher in HIV-1 infected individuals than in HIV-1 uninfected individuals [5].

Other biomarkers elevated during PHI were IP-10 and IL-18, with an association between IP-10 and a faster disease progression [3031]. Continued IL-18 and sCD14 elevation were also associated with clinical cART failure [32].

Although cART reduces immune activation and inflammation [522], these remain higher in HIV-1-infected individuals than in HIV-1-uninfected individuals, even after long-term viral suppression [33].

Studies have shown the benefits of initiation of cART during the acute or early infection [2467].

The early therapy decreases immune system damage and the establishment of a large viral reservoir [67].

HIV-1 infected patients who started cART during PHI presented an earlier immune reconstitution (CD4+ T cell count > 500 cells/mm3, CD4% > 30%, and CD4/CD8 ratio > 1) than cART in chronic patients [34]. Moreover, early cART decreases T cell activation [3735] and markers of inflammation [35]. Moreover, early ART is associated with a lower risk of development of non-AIDS morbidities [3637], and the study with the ANRS VISCONTI cohort demonstrated the possibility of a functional cure in individuals starting ART in primary infection [38].

In the present study, we compared the impact of cART on the levels of immunological markers between primary HIV-1 infected Brazilian individuals, who initiated cART, during the acute (Fiebig I-V) and early chronic phases (Fiebig VI). We evaluated CD4+ T cell counts, CD4/CD8 ratio, CD4+ and CD8+ T cell activation before (Pre-ART) and six (M6 ART) and 12 months (M12 ART) after cART initiation. We also evaluated plasmatic markers of inflammation and monocyte/macrophage activation at Pre-ART and M6 ART and total HIV-1 DNA at M6 and M12. We hypothesized that earlier cART would normalize levels of biomarkers associated with disease progression and death in HIV-1 infection.

More information: Kim Anthony-Gonda et al. Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model, Science Translational Medicine (2019). DOI: 10.1126/scitranslmed.aav5685

Journal information: Science Translational Medicine


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