Major Clinical Findings By California AIDS Team: HIV Does More Than Kill Off T Cells

The scientists--from the Gladstone Institute of Virology andImmunology at UC San Francisco and from UC Berkeley--reporttheir research results in the January issue of NatureMedicine. The study involved 21 patients.

"These studies focus our attention on the ways that HIVinfection might stop the production of new T cells," saidJoseph M. McCune, MD, PhD, senior study investigator andassociate professor within the Gladstone Institute at UCSF. "To treat the disease, not only do we need potentanti-retroviral drugs to stop the virus from spreading anddestroying T cells, we may also need additional therapies toensure that T-cell production starts anew."

The findings are significant in understanding the puzzle ofT-cell turnover in the HIV population, an area that hasremained controversial among leading AIDS researchers whohave proposed different theories to explain why T-cellcounts decrease during the course of HIV disease.

Scientists use "turnover" to describe the natural process ofT-cell death and new cell production that takes place in allindividuals but that is altered after HIV infects the body. The precise mechanism that HIV uses to derail the differentparts of this process have been unclear, but the end resultis a collapse of the immune system that makes the bodyvulnerable to the opportunistic infections that causefull-blown AIDS.

It had been previously thought by many investigators thatHIV decreased the T-cell count by causing the destruction ofthese cells. The new studies indicate that a more importantcontribution to disease may be the ability to stop T-cellproduction.

Using a new diagnostic tool, the research team determinedthe rates of production of two types of T cells--CD4 andCD8--that are major players in the immune system and primetargets of HIV. The technique was developed by McCune andMarc Hellerstein, MD, PhD, the lead investigator of thestudy and an associate professor at UCSF and at UC Berkeley.

"We found that the virus had an impact on both the rate ofT-cell production and the rate of their destruction,"Hellerstein said. "But it was the body's ability to producenew cells that was most important in determining T-cellcounts."

Study participants included both men and women, and all werepatients in the General Clinical Research Center at SanFrancisco General Hospital Medical Center. They representedthree groups: HIV-negative and healthy, HIV-positive who hadnot undergone anti-HIV drug treatment, and HIV-positive whohad completed a 12-week course of effective treatment withthe potent antiretroviral drugs known as protease inhibitorsafter previously being untreated.

Major findings include:

For the first time, the daily rate of production of normalCD4 and CD8 T cells was directly measured in HIV-negativeadults.

In untreated HIV-positive patients, CD4 and CD8 cells werebeing destroyed at a more rapid pace than in HIV-negativesubjects and the body did not compensate by increasing therate of production above the normal rate. Accordingly, theT-cell count decreased.

In HIV-positive patients whose virus was suppressed bypotent therapy and whose T-cell counts increased, the rateof new cell production increased dramatically. The rise innew cell production was responsible for the increase inT-cell counts.

Warner Greene, MD, PhD, director of the Gladstone Instituteof Virology and Immunology, called the findings surprisingand noted that, "They promise to reshape our view of T-celldynamics in HIV infection. These results have importantimplications on new approaches to therapy aimed ataugmenting T- cell production rather than simply blockingT-cell destruction."

Crucial to the study was the new diagnostic tool that makesit possible to mark any human cell with a nontoxic label atthe time of cell division and then to use the label todirectly measure the numbers of new cells produced.

In this study, the label was incorporated in a speciallyformulated glucose solution that was administered topatients intravenously. After passing through complexbiochemical pathways, the label attaches itself to the DNAof dividing cells.

The researchers took periodic blood samples from patientsduring the infusion and during the next two- to three-weeks. With the label serving as a marker for newly divided cells,they analyzed samples by using a cell sorter to isolate purepopulations of circulating T cells and a mass spectrometerto measure the number of labeled cells.

Because the labeling was carried out in living people, theresults serve as the first direct clinical evidence of cellproduction in the human bloodstream. In the past, cellgeneration could not be directly measured in clinicalstudies because techniques involved radioactive or toxicchemicals unsuitable for human consumption.

Based on the study findings and previous work, McCune saidit appears that HIV may disrupt T-cell production in two keyways.

First, virus infection may short-circuit the division ofmemory T cells, whose function is to ward off foreigninvaders that the body encountered in earlier years. Withouta continuous supply of these cells, the immune systemdoesn't "remember" that it can successfully fight offprevious enemies, and a person becomes susceptible to avariety of infections.

Second, virus infection may prevent the production of new Tcells from the bone marrow and the thymus, the major organsof T-cell production.

In either case, the immune system would collapse and theHIV-infected patient would become immunodeficient, McCuneexplained.

"It remains unclear whether all HIV-infected patients willbe able to increase T-cell production and restore theirimmune systems after treatment. For those who cannot,additional therapies may be required," he said.

Study co-investigators are Mary B. Hanley, BS; Eric Wieder,PhD; Diane Schmidt, BS, from UCSF and the GladstoneInstitute; Derek Macallan, MD, PhD; Steven Deeks, MD, andRebecca Hoh, RD, UCSF; Richard Neese, PhD, UCSF and UCBerkeley; and Denise Cesar, BS; Scott Siler, PhD, andChristina Papagoorgopoulos, PhD, UC Berkeley.

The research was supported by grants from the NationalInstitutes of Health, the UCSF Center for AIDS Research,SpectruMedix, Inc., and the UCSF/Macy's Center for CreativeTherapies and by funds from the J. David GladstoneInstitutes.

The Gladstone Institute of Virology and Immunology, foundedin 1991, focuses its research on HIV and AIDS. TheInstitute is one of three that make up the J. DavidGladstone Institutes, a private biomedical researchinstitute affiliated with UCSF and named for a prominentreal estate developer who died in 1971. His will created atestamentary trust that reflects his long-standing interestin medical education and research.