Location of cyclin T1 (green) and Cdk9 (red) in cells.
Dr. Andrew Rice, who has been conducting HIV research since the mid-1980’s, has been studying the transcription part of the virus replication cycle. This is the step in which the virus Tat protein and a large “factory” of cellular proteins that make RNA copies of the virus from the virus DNA that is integrated into the cell’s DNA. Several years ago, his group discovered that the virus’ Tat protein does not function alone, but requires two cellular proteins that are called Cdk9 and cyclin T1, that act together to modify the cellular transcription factory and make it much more efficient at making virus RNA copies. These two cellular proteins are therefore essential for HIV to replicate and represent potential drug targets.
Dr. Rice’s group is continuing to study how Cdk9 and Cyclin T1 are regulated in the two major types of immune system cells that HIV infects – CD4+ T cells and macrophages. His laboratory has recently found that a specific phosphorylated form of Cdk9, that is essential for its catalytic function, is highly regulated in CD4+ T cells. This regulation is likely to have profound effects on HIV replication levels. Additionally, his laboratory has identified a microRNA in monocytes that inhibits Cyclin T1 protein expression. This microRNA therefore appears to play a role in the repression of HIV replication in monocytes. Increased understanding of how Cdk9 and Cyclin T1 work in cells and the ability to control their activity and interaction with Tat could potentially be used to develop new anti-HIV therapies that would target a step in the virus replication cycle for which there are currently no drugs.
Although considerable effort has been made, a vaccine to protect against HIV infection is not yet available. An effective vaccine against sexual transmission of HIV should elicit two types of immune responses - systemic and mucosal. Dr. Cathy Yao is taking a novel approach to develop such a vaccine and to further understand interactions between vaccines and components of the host immune system. Her group is using an immunogen called simian-human virus-like particles (SHIV VLPs) in their HIV vaccine studies. SHIV VLPs are non-infectious virus-like particles that contain HIV proteins but do not contain HIV genetic information. This vaccine can induce both types of immune responses. Although other groups are working on HIV virus-like particles as vaccines, Dr. Yao’s approach is unique in that: (1) it incorporates a protein from the outer surface of influenza (flu) virus into the HIV virus-like particles so the vaccine can be delivered to a specific site of the respiratory tract to produce a mucosal response, (2). It can be modified by incorporating other costimulatory molecules to enhance the binding and activation of the antigen-presenting cells, such as dendritic cells and B cells, so that it can induce potent immune responses, (3) it can produce both humoral ( antibody) and cellular ( cytotoxic T cell) immune responses against HIV, (4) it induces immune responses at other mucosal sites especially the vaginal site, which prevents HIV from sexual transmission in females, and (5) it activates immune responses without requiring CD4 + T cells – the cells destroyed during HIV infection, and therefore it can be used as a therapeutic vaccine for existing AIDS patients. The idea is that people will receive the vaccine via an intra-nasal spray which will allow the vaccine to target the mucosal layer of a person’s respiratory tract. It is thought that the vaccine may be used in both prevention of HIV infection and therapy of those who have already become infected with HIV. Currently, Dr. Yao and her colleagues are testing how well this vaccine works in small animal models and are trying to understand the molecular mechanisms of the vaccine. They are also testing their modified SHIV VLP vaccines on non-human primates models. Successful results in monkey trials would be followed by vaccine trials for human use.
Currently, there is not a good animal model system in which to study all aspects of HIV infection. Improved, relatively inexpensive animal model systems would be extremely useful to researchers, because it would allow them to explore more thoroughly how HIV causes disease and also to better evaluate candidate drugs and vaccines. Two researchers in MVM are using different approaches to studying HIV in animal model systems. Dr. Jason Kimata, whose laboratory is interested in studying strategies used by HIV to reproduce and survive in the host, is using experimental infection of macaques with simian immunodeficiency virus (SIV) as a model for HIV infection and disease. Like HIV in humans, SIV causes AIDS in Asian macaque species. Using this animal model, Dr. Kimata and colleagues have determined that SIV, and by analogy HIV, mutates and becomes more virulent during the course of an infection. They are identifying the changes in the SIV mutants that correlate with increased viral replication and disease-causing potential. They have found mutations that enhance replication of the virus by enabling the virus to evade, exploit, and suppress the immune response of the host. Furthermore, the changes in virulence of SIV may occur because of the host immune response against the virus. Complementary studies are being conducted with viruses isolated from cohorts of HIV infected individuals. Dr. Kimata’s lab is also using the SIV model to better understand how HIV may be transmitted from one host to another and why some primate species are able to resist infection by HIV and SIV, while others are susceptible to infection and disease. The Kimata group’s goal is that the results from these studies will help define new ways to prevent HIV infection, inhibit its replication, and provide insight important to the development of a globally effective vaccine.
Dr. Richard Sutton and members of his laboratory are working on developing a small animal model system – the mouse – in which to study HIV. Researchers often prefer to work with small animal models because of their lower cost and the ability to study a larger number of animals. HIV does not naturally replicate in mouse cells because they lack versions of certain human genes that are required by HIV to reproduce. Dr. Sutton’s lab has determined that introduction of a particular single human chromosome into mouse cells allows HIV to complete one of the steps in the HIV replication cycle that normally does not occur in mice. They are currently developing methods to identify the specific genes responsible for this effect and hope to use this knowledge to create a mouse model for the development and testing of candidate HIV vaccines and for other studies.
Ironically, the very factors that have made HIV a successful virus in causing an epidemic, may turn out to be useful to researchers for other purposes. Because of the ability of HIV to infect types of human cells that other viruses cannot infect, a disabled version of HIV might be useful as a vector for gene therapy. Dr. Sutton’s laboratory is working to develop such HIV vectors and has been able to introduce genes into human blood stem cells using these vectors. Dr. Sutton and his group are actually trying to turn HIV against itself, by using these vectors to introduce genes that counteract HIV into cells. They are currently in the process of evaluating this approach to see how well the introduced genes work against the virus.
In addition to the HIV projects headed by individual researchers, one of a nationwide network of AIDS Research Centers, the Baylor-UTHouston Center for AIDS Research (CFAR) exists within MVM. The CFAR is a federally funded program that facilitates research aimed at understanding, detecting, preventing, and treating HIV/AIDS. The Baylor-UTHouston CFAR has over 100 members located at BCM, UT-Houston Health Science Center, and other institutions within the Texas Medical Center (TMC) and is directed by Dr. Janet Butel, Chair of MVM. Particular strengths of the Baylor-UTHouston CFAR include pediatric AIDS clinical studies, basic virology, and education programs. The Baylor International Pediatric AIDS initiative headed by Dr. Mark Kline, a CFAR member, has established high-quality care centers which provide services for pediatric AIDS patients in a network of countries including Romania, Botswana, Lesotho, Swaziland, and Uganda.
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