Passive Immunization with a Broadly Neutralizing Antibody Provides Cross-Clade Protection
Passive immunization with the broadly neutralizing antibody (bNAb) HGN194 can completely protect rhesus macaques from challenge with a simian immunodeficiency virus (SIV)/HIV hybrid known as SHIV, according to a study led by Ruth Ruprecht, a professor of medicine at Harvard Medical School (1). It is the first evidence that any bNAb can completely protect macaques from a challenge virus that has Env from a different clade than the virus that elicited the bNAb, says Ruprecht. Because HGN194 is an antibody that recognizes the V3 loop of Env, “our study identified V3 as a protective epitope, even in a situation of cross-clade mismatch,” she adds.
HGN194 was isolated last year from a long-term nonprogressor infected with a clade A/G HIV by a group led by Antonio Lanzavecchia, the director of the Institute for Research in Biomedicine (see Research Briefs, IAVI Report, Jan.-Feb. 2010).
Ruprecht and colleagues used an R5-tropic SHIV called SHIV-1157ipEL-p that has a clade C HIV Envelope isolated from a six-month old child from a mother-infant cohort in Zambia. Four animals received a high dose of 50 mg/kg of HGN194 intravenously, followed a day later by a single high-dose, intra-rectal SHIV challenge and another high dose of HGN194 delivered intravenously a week after that. Two animals received the same regimen except that the antibody dose was 50-fold lower, and four control animals only received the SHIV challenge.
All four untreated control animals became infected. In contrast, all four animals that were infused with the high dose of antibody showed no sign of infection even when the researchers used polymerase chain reaction assays to look for virus in the lymph nodes, suggesting they were completely protected. One of the two animals that received the low dose of antibody was also completely protected, while the other got infected but had a lower and delayed peak viral load compared with controls.
HGN194 did not react with the rhesus macaques’ own tissues and was degraded relatively slowly, with a half life of almost a month—much longer than the half lives of other bNAbs in rhesus macaques, such as 4E10, 2F5, and 2G12.
The researchers also found that the four animals that received the high dose of HGN194 (all of which were completely protected) had memory CD4+ and CD8+ T cells specific for HIV Gag. This was surprising because the animals did not show any signs of virus. Even after eliminating cells expressing CD8 from the animals, there was no virus, suggesting that there was no reservoir of infectious virus in the animals that had been kept in check by the CD8+ cells.
Another explanation for the cellular immune responses to Gag is that HGN194 antibody molecules covering the viral particles may have been taken up by antigen presenting cells such as dendritic cells, which could then have presented viral proteins, leading to the observed CD4+ and CD8+ memory T-cell response. Ruprecht says this is the most likely mechanism because it depends on the presence of antibodies and is therefore consistent with the observation that only the four animals that received the high HGN194 antibody dose showed these immune responses.
Ruprecht’s most recent study is not the only observation of immune responses against HIV after a “protected challenge”—a virus challenge that an animal is completely protected from by an intervention such as passive immunization. Her own group made a similar observation in a study where neonatal rhesus macaques were passively immunized as post-exposure prophylaxis (2). And in 2008, Robin Shattock and colleagues also observed cellular immune responses in rhesus macaques that were protected from rectal challenge after receiving a rectal microbicide that contained the antiretroviral tenofovir (3; see A Flurry of Updates from Keystone, this issue). Shattock, who was not involved in Ruprecht’s study, says it “adds weight to the concept that protected challenge can induce an immune response.”
Ruprecht says one important implication of her study is that it establishes the V3 loop as a conserved vaccine target. “The V3 loop had been discounted for many years,” she says, because it was thought to change too much to serve as a target for vaccine development. Susan Zolla-Pazner, a professor of pathology at New York University’s Langone Medical Center who has been studying the Env V3 loop for many years, says there has been general resistance to the idea that anti-V3 antibodies can play a protective role or should be among the desired antibodies induced by a vaccine, because early studies suggested that such antibodies have a very narrow specificity.
“The field has been extremely slow in ‘unlearning’ or modifying this idea,” Zolla-Pazner says, even though more recent studies from her and from other labs have shown that some anti-V3 antibodies have a very broad specificity. “[Ruprecht’s study] demonstrates that V3 is one of the epitopes that should be targeted by a vaccine,” she adds. —Andreas von Bubnoff
1. PLoS One 6, e18207, 2011
2. J. Infect. Dis. 189, 2167, 2004
3. PLoS Med. 5, e157, 2008