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aids research institute at ucsf laboratory of clinical virology

Critically Important Expertise and Resources for HIV Research

To understand and combat civilization’s most notorious virus, HIV, researchers need tools that are as adaptive as the virus itself and need them wielded with the determined focus that the virus seems to exhibit. So, at San Francisco General Hospital (SFGH) and the University of California, San Francisco, where the intensity of the clinical and research focus on HIV-1 is perhaps unrivaled, it’s not surprising to find that the expertise offered by the AIDS Research Institute at UCSF Laboratory of Clinical Virology (LCV) is being honed constantly as it supports the cutting edge of research and patient care.

The convergence of essential resources makes San Francisco an important site for clinical research. As Jason Barbour, a clinical researcher at the HIV/AIDS Division at SFGH, explains, “Having a representative population of persons with HIV allows you to do highly informative, very powerful clinical research studies. Having those cohorts together with core labs such as the Laboratory of Clinical Virology is a very powerful combination.”

In its current form, the laboratory is administered by the ARI and is largely self-funded. At any one time its hard-working laboratory staff of eight supports 50 to 70 research studies. “Those studies extend from small, high-risk research pilot studies to multi-million-dollar, international clinical trials,” notes Teri Liegler, research director of the LCV. To develop new tests and assays, the laboratory relies upon grants from institutions such as the National Institute of Health’s Center for AIDS Research to invest in staff and new equipment. The lab rounds out its services by performing specialized clinical tests used for the management of patient treatment, from which it generates about 15% of its income.

Zoila Angeles, CLS (ASCP), a clinical laboratory scientist at the ARI-UCSF Laboratory of Clinical Virology.

Looking at the productivity of the LCV, it becomes clear that it is more than the sum of its parts. It is more than a repository of expensive equipment—DNA sequencers, thermocyclers, and robotic viral load–measurement devices. And its staff members are more than just operators of these instruments. Describing his experience of working with the LCV, Barbour says, “One of the fantastic things about the lab and about Teri Liegler is that you can approach her to say, ‘I have a specific, special need, a custom idea in mind.’ She will always sit down with you and talk to you about it, and most often be able to accommodate you. And that’s possible because she has such a deep body of expertise herself in basic science research, both in HIV and in other disciplines, such as immunogenetics.”

In a current study, Barbour wants to look at how two HIV-1 genes participate in the earliest stages of HIV infection and activation of T cells. To do this, he needs to examine the viral RNA. Sounds simple, but here’s the challenge: each of those genes can turn up in tens to hundreds of different versions within a single patient. Extracting such a large range of variants from 200 patient samples and accurately reading the precise sequences of their base pairs require extraordinary expertise. “We really need to work with people who have done a lot of that kind of work,” Barbour explains, “and the laboratory has done more of it than anyone else in San Francisco that I am aware of.”

For Barbour’s study, Ali Karaouni, one of the LCV’s research associates, has devised a set of oligonucleotide primers, a toolkit of “fishhooks” to catch most of the RNA gene products’ variants. Then he systematically scrutinizes the viral segments, base pair by base pair, with the kind of practiced eyes that ensure precise results.

Dr. Jason Barbour (L) works with LCV Research Associate Ali Karaouni.

Much prized and much touted, translational (or “bench-to-bedside”) research transforms experimental concepts in a lab into improved patient treatment. The Laboratory of Clinical Virology can point to numerous examples to which it has contributed. Liegler attributes this track record to working with highly sophisticated physician-researchers, the excellent flow of information around UCSF facilitated by organizations such as the ARI, and the sentinel nature of San Francisco’s population of HIV/AIDS patients who have received leading-edge treatment for more than a decade.

As a case in point, one study led by Robert Grant of the Gladstone Institute of Virology and Immunology (and medical director of the LCV) together with Frederick Hecht of UCSF helped initiate an improvement in the standard of care for patients by uncovering a previously hidden source of drug resistance in the HIV/AIDS community. With the help of the LCV, the principal investigators determined that drug-resistant HIV-1 mutants could be transmitted from a person living with AIDS undergoing antiretroviral treatment (ART) to another person who had never received ART. As a result, the U.S. Department of Health Services now recommends HIV/AIDS patients be tested for drug-resistant viruses before initiating therapy. By catching the presence of any resistance at the outset of treatment, the optimum ART regime can be prescribed for them.

The laboratory also supports “bedside-to-bench” research, helping researchers find the molecular biology underpinnings to clinical observations. Several years ago, Grant, Barbour, Steve Deeks, Jeff Martin, and colleagues noticed that even when ART fails to completely suppress the replication of some HIV-1 mutants in patients, those patients who remain on the seemingly ineffective treatment regimen appear healthier than those patients who discontinue it.

Careful viral sequencing by the LCV helped reveal that when ART is suspended, the HIV-1 population that becomes dominant is the more common, more virulent form. When it replicates rapidly, it depletes the patient’s immune system more rapidly than the less virulent, resistant form of HIV-1. If ART is continued, the resistant virus dominates and helps suppress the growth of the more virulent form. As a result, those patients appear less ill, even while the resistant virus continues to replicate.

While responding to the needs of researchers by innovating and pushing the bounds of assays for research, the LCV must also operate under stringent regulatory standards. In 2001, Grant and Liegler decided to sharpen the laboratory’s clinical capabilities and initiated the clinical licensing process in anticipation of tightened requirements for laboratories participating in clinical trials.

Clinical certification also enables the laboratory to provide better patient care by offering genotypic resistance testing. It’s currently the standard of care to identify which drug-resistant HIV-1 variants a patient may have so that the most effective ART can be prescribed. But it requires such a high level of expertise to reveal these mutations that confer drug resistance, few commercial and hospital clinical laboratories offer it.

LCV Laboratory Supervisor Jackie Javier.

Leading the eight-month effort to achieve clinical certification was Laboratory Supervisor Jacqueline Javier. Javier worked for 14 years as a medical technologist at the Palo Alto VA Medical Center before earning a master’s degree, engaging in research, and then contributing to the LCV’s mix of research and clinical work. For Javier, the mix is more satisfying than “putting a sample into a machine and waiting for a number to come out.”

Yet, performing complex tests upon patient samples with only one chance to do it flawlessly puts a lot of pressure on the laboratory’s staff. Liegler’s esteem for them is palpable when she remarks, “They can’t make a mistake, and they can’t have bad days.”

In an academic environment where individual achievement is more frequently recognized than collaborative efforts, it is uncommon to find the kind of motivation required to direct a core facility like the LCV. Liegler finds her reward in partnering with the high-caliber physicians and scientists. “They are the movers and shakers of HIV/AIDS research, and being able to work with them is very exciting. I like to be very collaborative, and I like working in lots of different areas. To me, it’s the perfect job.”

In the end, what does the ARI Laboratory of Clinical Virology offer that enables HIV/AIDS researchers and clinicians to provide the very best to patients? “High-quality people and innovation coupled with methodical, careful work,” reflects Liegler. “That—and keeping our ear to the ground in anticipation of what’s on the horizon—is what makes an effective translational research and core laboratory.”

The LCV staff (L–R): Sophie Stephenson, Yvonne Young, Teri Liegler, Zoila Angeles, Timothy Schmidt, Bernadette Barbante, Gerald Spotts, David Chung, Ali Karaouni, Jackie Javier (Missing: Robert Atchison, Robert Grant).

For further information, please see the ARI-UCSF Laboratory of Clinical Virology website or contact Teri Liegler at 415-476-2443 or email tliegler@sfgh.ucsf.edu.

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