State Health Department Scientists Demonstrate HIV "Shift"

Researchers: Combination Drug Therapy for HIV Preferentially Suppresses Viral Strains Associated with Rapid Disease Progression

Albany, March 12, 2001 – Scientists at the New York State Department of Health's Wadsworth Center have demonstrated that potent combination therapies for HIV, the virus that causes AIDS, leads to a change in the character of the virus as well as its quantity.

The study found that treatment of individuals with advanced HIV disease brought about a shift in the virus from the type often seen in rapidly progressive disease to strains associated with more stable infection. This finding may help to explain the dramatic success of combination therapy to treat HIV and may result in a new test to monitor therapeutic efficacy.

The research, led by Drs. Harold Burger, Barbara Weiser, and Sean Philpott of the Wadsworth Center, focused on participants in the Women's Interagency HIV Study, a National Institutes of Health sponsored investigation of the course of HIV infection in women. The study was published in the February 20 issue of The Journal of Clinical Investigation.

The scientists asked how treatment with combination therapy affects a crucial characteristic of HIV, how the virus gains entry to a cell. To infect a human cell, HIV must interact with both a primary receptor on the cell surface, called CD4, and a secondary coreceptor, either CCR5 or CXCR4. Coreceptor use plays a critical role in progression of HIV disease. Soon after infection most individuals have HIV strains that use CCR5 (R5 strains), but later CXCR4 using strains (X4 strains) may emerge. This shift predicts immunologic decline and the onset of clinical illness due to HIV. Once X4 strains of HIV emerge in untreated patients, they usually persist for the duration of the disease.

Wadsworth Center investigators found that combination therapy led to a shift back to R5 viruses even after X4 strains had emerged. By developing a method to quantify the fraction of virus in the blood that uses each coreceptor, the scientists demonstrated that the proportion of X4 viruses, the strains associated with rapid progression, decreased significantly after initiation of combination therapy.

This study suggests that shifts in HIV coreceptor use may contribute to the reduction in the number of deaths and hospital stays in HIV infected individuals which have been observed following the introduction of combination drug therapy. Measuring the proportion of R5 and X4 viruses in a patient's blood therefore may serve as an effective test to help monitor the efficacy of HIV.

These findings may also explain an apparent paradox in the dramatic clinical response to combination therapy for HIV. Although early trials showed that treated individuals experienced both suppression of HIV in the blood and health benefits, more recent studies have found that infected individuals can derive clinical benefits without complete or prolonged viral suppression. The shift in the character of the virus during treatment to the virus type associated with stable infection may help provide a reason for the widespread beneficial response to therapy.

The next steps in this research are to define the precise link between the shift in HIV coreceptor use and the health benefits of drugs for HIV, and then to develop a quick, inexpensive laboratory test to determine the coreceptor use of virus from infected individuals.

Additional investigators contributing to this study include Christina M. Ramirez Kitchen, Kathryn Anastos, Esther Robison, William A. Meyer Ill, Henry S. Sacks, Usha Mathur–Wagh, and Cheryl Brunner.

3/12/01–23 OPA