A new study reports successful immunization against a so-far invincible “death star” strain of an HIV-related laboratory virus (SIVmac239) and another tough strain. The new approach also achieves long-term protection with a single dose, showing that gene therapy could allow broad and durable protection, based on a modified form of the CD4 protein that allows HIV entry into human cells.
More than a million people die of causes directly or indirectly related to HIV infection, and almost 200,000 childhood infections with the virus occur each year, according to UNAIDS statistics. The HIV virus is notorious for first entering and then killing off immune cells carrying the CD4 receptor, thus weakening the immune response to infection. Many attempts have been made to neutralize the virus by preventing its binding to the CD4 receptor, and thus to keep it out of the cell. This is typically done by introducing one or a few antigens from the HIV virus into the host body to provoke an immune reaction. Unfortunately, HIV reproduces very fast and mutates with equal rapidity, making the antigen used for vaccine production obsolete and the reaction time too slow.
The “death star” strain, in particular, has defied every vaccine developed until now. This is a simian immunodeficiency virus which infects monkeys and other primates, and has been used as a laboratory model for HIV because of their close similarity. HIV-related viruses can multiply only in primates and in humans.
In answer, a team of scientists at Scripps Research in Florida has come up with an innovative technique: beat the HIV virus using another harmless virus as a vector, to introduce a gene into the host which will produce a protein to bind and subsequently neutralize the HIV virus in the body.
The paper was published in the journal Science Translational Medicine on July 24, 2019.
Mathew Gardner, PhD, and Christoph H. Fellinger, PhD, worked closely with mentor Michael Farzan, PhD, co-chairman of the Scripps Research Department of Immunology and Microbiology, on the study. Image Credit: Scott Wiseman for Scripps Research
In the current work, the team used another laboratory strain that does not cause disease, namely, an adeno-associated virus (AAV) to express an engineered gene product called eCD4-Ig. This modified protein contains two co-receptors for the HIV virus, namely, CD4 and CCR5. In fact, CCR5 was first uncovered by the same team more than 10 years ago.
The AAV vector is inoculated into muscle in laboratory Rhesus macaque monkeys, and promptly infected muscle cells. As a result, they started to show high levels of the eCD4-Ig receptor protein. When the animal was then exposed to the SIVmac239 virus at high dosage, the virus migrated to the muscle cells expressing these receptors and was bound to them. As a result, it changes shape too early in the process, rendering it incapable of further infection.
This beautifully elegant approach served to protect the animal over the long term, whereas all the infected control animals died of SIV-related causes. AAV can thus be used to produce a protective vaccine unlike all known vaccines, antibodies and biologic drugs developed so far.
AAV is already well-known for its ability to introduce therapeutic genes to treat conditions like inherited retinal disease and spinal muscular atrophy, for both of which conditions it has FDA approval. Lead author Michael Farzan comments that the new study showcases the potential of AAV to develop many protective vaccines, and in particular to stop HIV infection using eCD4.
The vaccine is still at an early stage of development. For instance, when the exposure load was increased by 2, 8, 16 and 32 times the original infective dose, the immunized animals did eventually die of the infection. Even then, the number of viruses in their bodies was significantly lower at peak point, compared to unimmunized animals. The researchers also reported that viruses which had CD4 mutations preventing their binding had a survival advantage in this situation, with 75% of viruses in the dying immunized monkeys showing such changes. Other pathways protecting against the eCD4-Ig were harmful to the virus and therefore were not selected. The virus thus ttends to escape from the inhibition produced by eCD4-Ig binding by mutations at the gene, such as taking advantage of a single amino acid that makes eCD4-Ig different from the CD4 molecule in the monkey. This could be a mechanism of resistance, and much more work is required to bring the vaccine to maturity.
Farzan says, “We have solved two problems that have plagued HIV vaccine studies to date--namely, the absence of duration of response and the absence of breadth of response. No other vaccine, antibody or biologic protects against the two viruses for which we have demonstrated robust protection.”
The potential impact of the work in protecting people against the virus is immense, especially because of the ability to offer single-dose durable immunity, in places with limited access to medical care and with high vertical transmission rates. Farzan says, “We hope ultimately to prove that our approach is safe for both infected and at-risk persons at a cost that makes it useable everywhere.”
AAV-delivered eCD4-Ig protects rhesus macaques from high-dose SIVmac239 challenges
Matthew R. Gardner, Christoph H. Fellinger, Lisa M. Kattenhorn, Meredith E. Davis-Gardner, Jesse A. Weber, Barnett Alfant, Amber S. Zhou, Neha R. Prasad, Hema R. Kondur, Wendy A. Newton, Kimberly L. Weisgrau, Eva G. Rakasz, Jeffrey D. Lifson, Guangping Gao, Nancy Schultz-Darken and Michael Farzan, Science Translational Medicine 24 Jul 2019: Vol. 11, Issue 502, eaau5409, DOI: 10.1126/scitranslmed.aau5409, https://stm.sciencemag.org/content/11/502/eaau5409