HIV-Blocking Antibody Shows Promise, but Resistant Strains Break Through

One of the mechanisms being developed to help combat HIV is to prevent HIV-negative individuals, who are at risk of acquiring HIV-1, from becoming infected. One form of this preventative strategy is using broadly neutralizing antibodies (bnAbs)—administered intravenously—that could protect individuals from acquiring HIV-1. This could be most relevant for people with partners living with HIV, people at increased risk of HIV exposure (including individuals with ongoing sexual exposure risk), people who cannot or prefer not to use conventional PrEP, and among populations with high HIV incidence—for example, communities in regions of sub-Saharan Africa with substantial HIV transmission.

The antibody-mediated prevention (AMP) clinical trials were landmark trials in this area—the first to investigate whether intravenous infusion of a bnAb could prevent HIV-1 acquisition. The trials focused on the bnAb VRC01, which targets the CD4-binding site on the HIV-1 envelope (Env) glycoprotein. By binding to this region, VRC01 can neutralize susceptible HIV-1 strains and potentially prevent the virus from infecting host cells.

The broadly neutralizing antibody VRC01 has been thoroughly vetted as a potential prophylactic that could prevent people from becoming infected with HIV. Now, a new analysis of data from two clinical trials in the Americas and sub-Saharan Africa shows that the antibody initially provides strong protection, but that some strains of the virus can still cause breakthrough infections after treatment has stopped. The findings point to the importance of combining multiple types of antibodies to suppress HIV completely and to prevent breakthrough infections in vulnerable people.

This work is published in Science Translational Medicine in the paper, “Extended in vivo activity of VRC01 HIV-1 prophylaxis entails initial protective efficacy and subsequent breakthrough infections.”

Antibodies such as VRC01 are designed to halt the virus’ ability to infect its host initially through common sites of exposure. VRC01 has recently progressed to large-scale clinical trials, but scientists must test whether it can provide meaningful, real-world protection against the ever-evolving myriad strains of HIV.

In this new report, researchers parsed data from HVTN 704 and HPTN 085, two clinical trials where participants received infusions of VRC01 for 80 weeks. The two parallel antibody-mediated prevention (AMP) prevention efficacy trials evaluated whether intravenous infusion of the anti-CD4 binding site broadly neutralizing antibody VRC01 prevents HIV-1 acquisition.

The researchers focused their attention on the period after the treatment ended, from weeks 80 to 104. More specifically, they analyzed HIV-1 acquisition in AMP through the week 104 final study visit.

The researchers showed that VRC01 initially protected against HIV strains that were considered highly sensitive to the antibody, achieving a prevention efficacy of 66.3%. They write that against viruses considered highly sensitive to VRC01, “VRC01 prophylaxis maintained cumulative prevention efficacy of 66.3%, suggesting that the antibody successfully blocked or cleared these infections.”

As VRC01 concentration waned, suppressed viruses—often evolving greater resistance because of selective pressure—emerged as detectable infections. After week 80, some of the participants were still diagnosed with HIV that was considered more resistant to the antibody, and diagnoses were higher compared with the placebo group. They write, “In the post–week 80 period (after the final dose at week 72), HIV diagnosis and resistance to VRC01 were more frequent and greater in the VRC01 groups versus placebo.”

The findings, the authors explain, suggest that, “whereas single antibodies can block sensitive strains, multiple antibodies are likely required to prevent both viral escape and breakthrough infections.” The authors write that their results carry implications for the design and analysis of future trials of HIV-1 broadly neutralizing antibodies, such as the importance of testing for the virus far after infusions have ended.

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