Clara Cebrián Camarena, Sofía San Pablo López and Laura Mena Pascua
Original source: https://www.nature.com/articles/d41586-018-06773-8
Currently 36.9 million people worldwide are infected with HIV. The known medication in order to treat this disease has too many drawbacks. ART (the standard treatment) does not provide a cure as the drugs do not kill the infected cells. It also has a lot of side effects such as metabolic disorders. The researchers Mendoza, Bar-On and their collaborators are studying a new treatment that uses two antibodies to target a viral protein.
ART drugs can prevent viral production from the part of the reservoir termed the active viral reservoir, in which viral replication occurs. However, these drugs cannot target the viral reservoir that exists in a ‘dormant’ state, termed the latent viral reservoir. If these cells could be targeted, more-effective treatments might be possible.
The discovery of highly potent antibodies, termed broadly neutralizing antibodies (bNAbs) has been a revolution. These HIV-targeting antibodies can bind to and block a protein on the viral surface called Env, which is needed for HIV entry into host immune cells called CD4+ T cells.
Various clinical trials were developed in which it was tested the individual effect of two bNAbs (either 3BNC117 or VRC01). Initially there was a suppressed for 6–10 weeks, but then viral rebound occurred, and the studies reported the presence of antibody-resistant viral variants.
Mendoza and Bar-On decided to study if the combination of two bNAbs (3BNC117 and 10-1074) that target distinct sites on Env might decrease the probability of virus resistance occurring, and might control virus levels in HIV-infected people who did not receive ART during the trial period.
Both studies reported an impressive reduction in bloodstream HIV levels compared with levels at the start of the trial. Viral rebound took many weeks to occur, and when it did, there was little or no evidence that viruses were resistant to both bNAbs.
Mendoza and Bar-On found that when the bNAbs were introduced 2 days before ART was stopped, and further doses given 3 and 6 weeks later, virus in the bloodstream was suppressed to undetectable levels for a median time of 21 weeks before viral rebound.
One way to determine whether the characteristics of viral infection change after bNAb therapy is to compare the diversity of the nucleotide sequences that encode the Env protein before and after treatment. Mendoza and colleagues found that the rebounding viruses after antibody treatment had low sequence diversity, whereas a high degree of diversity has been observed in viral rebound after ART treatment.
How effectively might antibodies control virus levels without pretreatment with ART? In Bar-On and colleagues’ study, the treatment suppressed virus levels in the bloodstream for an average of 86 days. However, suppression was complete only in people who had low levels of virus in their bloodstream at the beginning of the trial.
Finally studies showed that, contrary to results in primates, there were no significant differences found in the reservoir size of the in vitro human virus-outgrowth. Nevertheless, longer and more-effective bNAb treatment and larger study groups might be needed to establish definitively whether bNAbs affect the viral reservoir.
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