Dr. Pollard Division of Infectious Diseases chief Richard Pollard has developed a robust clinical trials program at UC Davis.

The AIDS epidemic has raged for more than 25 years, but time has far from diminished the sense of urgency that surrounds this dreaded disease. With more than 32 million people worldwide living with HIV – the virus that causes AIDS – the creativity and commitment of talented UC Davis researchers, clinicians and collaborators in finding answers are more important than ever.

Today, those efforts significantly add to the scientific community's body of knowledge about the virus through clinical trials, investigations into mucosal immunity and analysis of AIDS in women and minorities. Partnerships with a highly regarded local clinic to provide community education and with the National Institute of Health-funded primate research center to support research add to the distinctiveness of the HIV/ AIDS research program at UC Davis.

The current research efforts rise from a foundation built starting in the late 1980s. UC Davis scientists led early efforts by identifying simian and feline immunodeficiency viruses, advancing the understanding of all retroviruses.

Through the 1990s, UC Davis scientists gained further knowledge of the natural history of both the human and simian AIDS viruses, including the potential for and mechanisms of cross-species transmission; demonstrated the feasibility of an AIDS vaccine; researched transmission mechanisms of such opportunistic diseases as feline leukemia; and identified the role of the body's own antibodies and cellular immune systems in fighting the virus.

Distinctive program

It's no wonder UC Davis holds a preeminent position internationally as one of the hotbeds of HIV/AIDS research.

"We have a unique situation in which animal research is conducted at a primate center with close collaborations among veterinarians who understand and have developed the monkey model and have used it to reflect what happens in humans," explains Richard Pollard, chief of the Division of Infectious Diseases in the Department of Internal Medicine.

"This, combined with our strengths in microbiology and immunology, particularly the study of mucosal disease, makes us unique among American academic and research institutions."

Pollard is among the top inter-national HIV experts. He is also recognized nationally as a leader in clinical virology, in particular the role of the immune system in the modulation of human viral infections. His investigations have focused primarily on HIV infections, herpes simplex virus and cytomegalovirus. And he is a leader in translational AIDS research, with many peerreviewed publications in this area.

"Today, UC Davis' HIV and AIDS research program is making important contributions on many fronts," adds associate professor David Asmuth, a clinician-scientist in the Division of Infectious Diseases.

"For instance, prior to Dr. Pollard's arrival at UC Davis in 2001, there were limited HIV clinical trials on campus. He brought a strong clinical research program here and has grown it unbelievably quickly. The program is widely recognized today for its quality clinical research."

Clinical trials

UC Davis' clinical research program has indeed blossomed over the last few years under Pollard's stewardship, with over 20 clinical trials currently active.

"Sponsors have increasingly come to us because of our good reputation in conducting trials," says Asmuth. "Several involve novel, state-of-the-art agents that promise to change the paradigm for how HIV patients will be treated in the future."

UC Davis is a leading site for studying raltegravir, a drug recently approved by the Food and Drug Administration that represents a leap forward in HIV care not seen since the introduction of protease inhibitors in 1995.

In addition, Pollard is the principal investigator for DermaVir, a novel therapeutic vaccine for HIV that is applied to the skin. If this works, patients already infected with HIV will receive this vaccine to boost their immune system so that anti- HIV medications can be delayed or suspended. Pollard is also the lead investigator for another therapeutic vaccine clinical trial scheduled to open this spring. His laboratory will serve as the coordinating center for the 10 other U.S. sites in this 300- subject international trial.

UC Davis was also a leading site for phase I trials of a Merck HIV preventative vaccine program that was recently canceled. "Although this vaccine was shown not to protect recipients from HIV infection during a parallel trial in Africa, we have no alternative but to keep trying," says Asmuth, who served as principal investigator for these trials at UC Davis.

Mucosal immunity

Mucosal immunity research involves analysis of the gut, where the virus has been found to wreak havoc within the mucosal immune system within just days of infection, doing its damage largely undetected by blood tests. Satya Dandekar, professor and chair of the Department of Medical Microbiology and Immunology, and her team have used an unusual combination of basic research in the lab, clinical trials with humans, and animal models at the primate research center to achieve their breakthrough mucosal immunity findings.

"The monkey model has been very important for high-quantity, indepth analysis of the complex gut immune system," she says. "In the early 1990s, it was the first to show – long before it was found in humans – that, within the first two weeks of infection, SIV (simian immunodeficiency virus) was targeting the gut immune system."

In 2006, Dandekar's group reported that HIV continues to replicate in gut mucosa, suppressing immune function in human patients – even when blood samples indicated that treatment was working. This finding becomes a persuasive argument in favor of starting therapy much earlier.

"I know firsthand that UC Davis is making important contributions that are making a real difference in the lives of people like me across the region and ultimately around the world."
— David Casey, CARES client and client advisory panel member

CARES partnership

Dandekar and other campus researchers rely on the nonprofit Center for AIDS Research, Education & Services, or CARES, for recruitment of study participants. Located in downtown Sacramento, CARES was founded in 1989 by UC Davis and three other area hospitals to provide comprehensive HIV/AIDS care to area residents. Its current patient load of 1,900 comprises the largest HIV population of any independent clinical group in Northern California.

CARES client and client advisory panel member Dave Casey, 45, has gladly participated in two recent studies of HIV in gastrointestinal mucosal lymphoid tissue, or GALT, including Dandekar's study. Both have required biopsies of the gut. "They've taken 48 specimens in two biopsies so far," he says. "I'm learning about my own system and receiving extra care and attention from top UC Davis specialists. Plus I'm contributing toward a cure."

Associate professor and CARES Medical Director Paolo Troia, one of several UC Davis employees who provide services at CARES, points out the many ties between the two institutions, particularly in education. "CARES provides many teaching opportunities, including a training area for infectious-disease fellows and a program for internal medicine residents and medical students. Campus experts, such as Dr. Pollard, routinely participate in our many patient and community education forums."

Women and minorities

Among the many UC Davis programs recruiting study participants from CARES is the California Research Center for the Biology of HIV in Minorities, established in 2005 with funding from the University of California's AIDS Research Program to carry out detailed biologic studies on immunologic and virologic differences in HIV-infected subjects of different ethnicities and in women. Led by Pollard, its goal is to describe differences that can be used to tailor customized therapies.

"The center was formed with the idea that women and minorities have been largely overlooked in published studies to date. We seek to address issues impacting HIV-infected populations that have been traditionally underserved," says Barbara Shacklett, one of the center's principal investigators.

She points out that the face of AIDS is changing, as the epidemic moves into inner-city populations, a group less studied in the first rounds of scientific literature.

"These patient cohorts are difficult to study because often they don't have good relationships with primary-care physicians, they might be lost to the system, or they may be jobless or homeless," she says.

Shacklett, also an expert on mucosal immunity, is teaming up with Dandekar, who serves as the center's pilot project core director, to study mucosal immunity in minorities and women.

"We're interested in studying how immune cells travel through the body and hover at certain sites, such as the gastrointestinal tract versus the blood stream. It's important to study what's going on in tissues where the virus hides out," says Shacklett, who is the principal investigator on the study.

The virus in action

The research focus for associate professor Thomas Huser, chief scientist at the UC Davis-based National Science Foundation Center for Biophotonics Science and Technology, is watching and tracking the virus itself as it moves from cell to cell.

In collaboration with the Mount Sinai School of Medicine, he and his peers are in the process of refining a technique that allows microscopic viewing of live, fluorescent HIV virus clones as they move into new, uninfected cells. The center's key contribution is development of techniques to create moving images of the virus in action, the first time that such images have been developed at such high resolution, length and video speed rates.

This work has enabled them to directly observe the passage of the virus from an infected to an uninfected cell. Such cell-to-cell transmission is orders of magnitude more powerful than the standard, much-documented cell-free transmission pathway.

Animal models

The federally funded California National Primate Research Center is one of eight centers around the country designed to study primates. Opened in 1962, it was well-positioned to assist when the AIDS epidemic began in the 1980s, and indeed, researchers called upon it as a resource almost immediately. Today, its researchers focus on such basic science as pathogenesis – the origin and development of the disease – and on preclinical development and testing of drugs, vaccines and microbicides.

Researchers Tom North and Paul Luciw, for example, are part of an NIH-funded consortium using animal studies to look at mechanisms of latency – the tendency of the virus to lay dormant and hidden within the body. Virologist Koen Van Rompay has demonstrated that the anti-HIV drug tenofovir is effective in protecting macaque monkeys against infection, a finding that holds great promise for pre-exposure use of tenofovir in humans.

"Many pathogenesis questions cannot be answered in humans," Van Rompay says. "For instance, it is often not possible to include a true placebo group in the study design. Well-designed studies in appropriate animal models can test novel intervention strategies rather rapidly, with relatively small animal numbers, and with inclusion of placebo groups."

The future

As new technologies emerge, UC Davis researchers and clinicians can be counted on to use them wherever appropriate in HIV research and clinical care. As just one example, in 2006 the campus started a stem cell research program that's now exploring the use of stem cell biology to engineer HIV-resistant lymphocytes, a development that, if brought to fruition, would be of great help to people with AIDS.

"UC Davis should be applauded and supported for its dedication to HIV research," says Casey, a long-time survivor who was diagnosed with HIV in 1989. "I know firsthand that its staff is making important contributions that are making a real difference in the lives of people like me across the region and ultimately around the world."