PURPOSE OF THE STUDY.
Although thousands of individuals become infected daily with HIV, attempts to create a protective vaccine have been unsuccessful. The identification of broadly neutralizing antibodies (bNAbs) from individuals with long-term HIV infection raised the possibility that such antibodies might be generated. Unfortunately, bNAbs are not particularly broadly neutralizing. This article reports the development of an engineered “immunoadhesin protein” with the potential to function as an effective HIV vaccine.
In vitro studies and rhesus macaque monkeys.
In vitro studies were conducted to assess the capacity of candidate protein constructs to neutralize HIV isolates, including those resistant to bNAbs. Subsequently, a candidate construct adapted to rhesus macaque monkeys was cloned into an adeno-associated virus (AAV) vector. This was then used to immunize macaques, which were then challenged intravenously with simian-HIV (SHIV).
Previous work with the immunoadhesin CD4-Ig demonstrated lower affinities than that of bNAbs for HIV envelope, and lower potency in neutralizing HIV isolates. These shortcomings were addressed by the addition of a CCR5 mimetic peptide to CD4-Ig, resulting in a final construct: CD4 domain-IgG1Fc-CCR5 mimetic or eCD4-lg. Variants of this construct were tested in vitro and shown to neutralize multiple neutralization-resistant virus at low concentrations, micrograms per mL levels, which are probably achievable in humans. Finally, eCD4-Ig was adapted to rhesus macaques (RHeCD4-Ig), and the gene for the resulting construct was cloned into an AAV vector. This was then administered intermuscularly to 4 macaque monkeys. No adverse effects were observed. These animals and four control animals were challenged intravenously with increasing doses of SHIV. The 4 control animals became infected; the 4 immunized macaques did not. RHeCD4-Ig could be measured in the serum of the immunized animals and the serum was effective in neutralizing HIV in vitro. Other studies cited indicated that these protective titers may be maintained for years.
An engineered protein that binds to the HIV envelope neutralizes a wide range of HIV isolates. The result was protection of the immunized animals against high-dose intravenous SHIV challenge. This suggests that AAV-delivered eCD4-Ig may function as an effective HIV vaccine in humans.
Why is HIV vaccine development so difficult? The prevention of viral infections, either through immunizations or by previous exposure, is primarily mediated by neutralizing antibodies. HIV evades immune defenses through a variety of mechanisms, including envelope variability that allows virus mutants to escape control by the host immune system, masking of critical regions of the virus envelope proteins by regions that are highly variable but also not critical for the function of the envelope, and viral inhibition of host immune defenses. These factors impair the generation of effective neutralizing antibodies. The current study demonstrates that a different approach may be warranted. The investigators created a protein construct that mimics CD4 and CCR5 interactions with the viral envelope protein. In effect, the engineered protein attaches to and blocks the envelope trimer on the surface of replication-competent HIV particles. The direct administration of such a construct would temporarily result in protection against acute HIV infection, but this would not be practical as a long-term solution for prevention at a population level. However, the investigators were able to “package” the gene for their protein construct into a viral vector that has been used for gene transfer therapy in other areas. There are significant challenges in taking this concept to clinical trials, but the novel approach described in this article may be eventually result in an effective HIV vaccine.
- Copyright © 2015 by the American Academy of Pediatrics