Nov. 30, 2015

Biology Professor Discusses Advances in HIV Research

Venigalla Rao, professor and chair of the Department of Biology, at work in the Bacteriophage T4 Lab.

Scholarly Article by Biology Lab Highlights Findings that May Lead to Potential HIV Vaccine

A recent article published by members of the Department of Biology's Bacteriophage T4 Lab is getting attention in the world of scholarly publishing. The findings and methods documented in the article have the potential to lead to the production of an HIV vaccine.

"A New Approach to Produce HIV-1 Envelope Trimers: Both Cleavage and Proper Glycosylation are Essential to Generate Authentic Trimers," was published in The Journal of Biological Chemistry in August, and soon became one of the top five most viewed articles from among those published in the third quarter of 2015, according to the journal's associate editor.

The article was also invited to be featured in World Biomedical Frontiers , "because of its innovation and potential for significant impact," according to the journal's editor Michael Yang. World Biomedical Frontiers highlights research with significant potential to improve health or to treat or prevent disease.

The findings of the HIV-1 envelope trimer paper are so significant that the research has led to the submission of five patent applications for the University. "The patents cover the methods we have developed to produce the HIV envelope trimer antigen that can be applied to any HIV strain. Further, it simplifies large scale production of very pure antigen for formulating future HIV vaccines," says Venigalla Rao, chair of CUA's Department of Biology and director of the T4 lab, which he founded in 1989.

The science documented in the article was largely the work of years of investigation by Catholic University doctoral student Wadad Alsami, the study's lead author, a member of the T4 lab. Other members of the lab are also authors: postdoctoral fellows Marthandan Mahalingam, Neeti Ananthaswamy, graduate students Christopher Hamlin, Guofen Gao, undergraduate student Dalia Flores, and Rao.

Over the years, Rao and his lab members and collaborators at other research institutions have published landmark papers and received millions of dollars of grant funding from the National Institutes of Health, the National Science Foundation, the Bill and Melinda Gates Foundation, and others.

The work of Rao's lab, which has gained an international reputation over the years, has been aimed at generating knowledge about the nanoscale packaging machine of the bacteriophage T4 virus that pumps DNA into the virus head. Rao and his fellow researchers have discovered mechanisms that can be manipulated to deliver therapeutic molecules such as DNA or a protein into cells of the body, including an HIV vaccine. These could lead to novel nano-medical therapies in the future.

"One of the key aspects of developing any vaccine is to design the target pathogen antigen. Our T4 technology can then be customized to deliver the antigen to generate robust immunity against the pathogen," explains Rao.

"In the case of HIV, the most challenging aspect of HIV vaccine development is designing the target antigen that can elicit the right type of immune responses to prevent HIV infection. The field has struggled with this for a long time. After many failures of human clinical trials, we still don't know for sure what the right antigen is.

"Our current work allows production of one of the antigens, the HIV-1 envelope trimer that is now considered to be the right antigen. Its structure mimics the trimer that is naturally present on the surface of the HIV virus. The closer in its structure to the natural structure, the better it is supposed to be for eliciting the right type of immune responses. This work, thus, not only helps preparing our T4-HIV vaccine formulations but also helps other researchers using other modalities to prepare HIV vaccine candidates," explains Rao.

The study of the HIV-I envelope trimer as a candidate for designing an effective HIV vaccine has been Wadad's passion and the focus of her doctoral dissertation. In simple terms, she describes a trimer. "HIV has spikes on its surface, composed of two types of proteins and three copies of each protein. That's why we call it a trimer," she says.

"When the HIV particle first interacts with the host cell, the top part of trimer is what attaches to host cell. And that first interaction is what allows HIV to enter the host cell. Being able to successfully replicate the trimers can lead to a vaccine. We are now using this to immunize rabbits and depending on the response, immunization of monkeys and human trials," says Wadad.

Getting to this point, she says, has been challenging and has come with much trial and error. But she admits that's a good thing. "We tried so many different things that did not work. But that's OK. You learn more when things don't work rather than when they do work. That's what gave me the skill and knowledge to get to this point."

A Few Questions for Dr. Rao

As World AIDS Day, Dec. 1, shines a spotlight on advances in HIV and AIDS research, Venigalla Rao, director of CUA's T4 lab, answers a few questions. His research team is engaged in basic research that may lead to, among other preventive therapies, a potential HIV vaccine.

What motivates you and your research team? Our research team is very excited about understanding how an infectious virus is assembled and translating this knowledge into novel nano-medical therapies to treat infectious and genetic diseases.

When you attend international AIDS conferences and talk with other researchers, what is the scientific community most optimistic about when it comes to treating and defeating this disease? Advances in anti-retroviral therapies are dramatically changing the management of HIV patients, more as a chronic disease. Cocktails of anti-retroviral drugs are now available that can essentially block HIV replication to a minimum. The sooner these drugs are taken after HIV infection, the greater the benefit to minimize the progression of HIV pathology. These drugs may also be taken as prophylactics by at-risk individuals to prevent the spread of HIV infections.

How close are we to an HIV vaccine? Rapid progress is being made on empirical as well as rational design of vaccines, but we are not anywhere close to a deployable HIV vaccine yet. Unfortunately, HIV presents unusual scientific challenges that could easily make one pessimistic about a universal HIV vaccine. However, it is also a great motivator to learn more deeply about the basic biology of the virus and overcome these challenges. I am very optimistic that we will have an effective HIV vaccine candidate(s) in the next decade.