Three broadly neutralizing antibodies (bNAbs) working together in an HIV-positive person may explain how this individual controlled HIV for 30 years without antiretroviral therapy (ART). Almost 90% of HIV strains circulating in this person remained sensitive to at least one of the three bNAbs.
In some people infected with HIV, antibodies that potently neutralize a range of HIV strains develop over time. When passively transferred to mice or monkeys, these bNAbs can treat or prevent HIV infection. But because viral strains infecting an individual and that person's antibodies evolve together, bNAbs that evolve during chronic infection typically do not control HIV in that person. To learn more about this coevolution, researchers from Rockefeller University and colleagues at other centers analyzed antibodies and viral strains in a person who maintained low viral loads for 30 years without ART.
Diagnosed with HIV in 1986, this individual controlled HIV replication well without ART. Researchers first detected HIV-neutralizing activity in this person in 2006, when the viral load lay below 400 copies/mL. That activity increased through 2010 and remained broad and potent in subsequent years. During that time, the investigators detected three different bNAbs -- BG1, BG18 and NC37 -- which neutralize HIV by binding to three nonoverlapping sites of the HIV envelope protein. BG18 is the strongest member of its bNAb class. Individually, BG1 neutralized 37% of HIV isolates in a 118-isolate panel, BG18 neutralized 64% and NC37 neutralized 33%. Combined in a 1:1:1 ratio, the three bNAbs neutralized 81% of the 118 isolates.
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Single-genome sequencing of HIV in samples collected from this person over nine years identified a diverse group of 35 circulating viruses. Of these 35 viruses, only four proved resistant to the combined three bNAbs. The other 31 viruses remained sensitive to at least one of the three bNAbs.
Next, the research team tested the three bNAbs against an HIV lab strain used to infect humanized mice. A 1:1:1 combination of the three bNAbs reduced viral loads by an average 1.48 log10 copies/mL (30-fold) soon after bNAb administration. With twice-weekly dosing for three weeks, six of the nine mice had an undetectable viral load after three weeks. The investigators conclude that the combined bNAbs "mediate potent and durable suppression of viremia in humanized mice infected with HIV-1YU2."
The bottom line, the researchers propose, is that a high proportion of viruses sensitive to the three bNAbs coexisted with those bNAbs for long periods. In other words, for many years infecting viral strains did not evolve to avoid neutralization. This coexistence of sensitive viral strains and multiple bNAbs may explain how this 30-year elite controller largely constrained HIV replication and "suggests that combinations of bNAbs may in fact be able to contain HIV-1 infection in humans."