HIV infects subset of T cells leading to depletion, Gladstone researchers find

The battalion of CD4+ T cells, which fight HIV and other pathogens, needs new
recruits to replace the cells that fall. Researchers at the Gladstone Institute
of Virology and Immunology and co-authors have found that these recruits,
called naive T cells, are susceptible to the bullets of HIV infection even
before they step onto the battlefield.

The study, published in the October 17 issue of the journal Immunity, is among
the first to show that HIV can indeed infect naive T cells and brings some
resolution to what was the subject of great debate among HIV researchers. The
finding helps to explain how T-cell numbers diminish to levels that leave the
body susceptible to opportunistic infections characteristic of AIDS.

“The collapse of the CD4+ T-cell system is the cardinal feature of AIDS, so
understanding which subsets of T cells can be infected is important in
providing a clear picture of how HIV reduces the number of T cells,” said
senior co-author Mark A. Goldsmith, MD, PhD, associate investigator at
Gladstone and UCSF associate professor of medicine.

CD4+ T cells are divided into two basic classes-naive cells and memory cells.
Once exposed to a pathogen, naive cells become memory cells, which signal other
immune system cells to mount an attack on the offending pathogen. Conventional
wisdom was that HIV infected memory T cells nearly exclusively.

Such thinking resulted from studies that used T cells isolated from blood,
Goldsmith said. But only 2 percent of all immune system cells are circulating
in the blood at once, so these cells may not be sufficiently representative.
Also, culturing these cells requires the use of artificial stimulants, changing
the way they react to the environment.

Goldsmith and lead author Daniel A. Eckstein, a UCSF Biomedical Sciences
Program graduate student at Gladstone, instead focused on the cells found in
lymphoid organs, such as the spleen, lymph nodes, and tonsils, where most
immune system cells are located. Because cells in these tissues can be cultured
without artificial stimulants, their behavior closely mirrors that found in the
body.

Before this study, other researchers had claimed to have isolated HIV-infected
naive cells from infected individuals. Some HIV researchers, however, suspected
that these cells were merely infected memory cells that had reverted back to a
naive character. The current study clears away those suspicions and shows that
naive cells themselves can indeed be infected.

In one experiment, the researchers infected naive cells with HIV. In addition,
they added BrdU, a substance that shows up in cells that have divided.
Generally, naive cells don’t divide. Memory cells do. About 14 percent of the
naive cells were infected, while only 2 percent were labeled with BrdU. This
shows that the vast majority of the cells that were infected had not divided.
The infected cells were naive cells and not dividing memory cells.

The discovery could change the way physicians think of the way HIV infection
leads to AIDS. Infected naive cells are a source of HIV, helping it to spread
throughout the body. These infected naive cells also die and then are no longer
available to replenish the immune system.

Without these CD4+ T cells, the virus “eliminates the ability of the immune
system to respond to the opportunistic infections characteristic of AIDS,” said
Eckstein, who is also a medical student in UCSF School of Medicine’s Medical
Scientist Training Program.

The specific HIV strain that the researchers employed is classified as an “X4”
virus; such strains are found in 50 percent to 90 percent of patients during
the later stages of infection. Eckstein said that the study underscores the
importance of developing a drug to antagonize a specific protein involved in X4
HIV infection.

Gladstone researchers also involved in the study include Michael L. Penn, PhD,
former graduate student in the UCSF Biomedical Sciences Program and medical
student in the Medical Scientist Training Program in the UCSF School of
Medicine; Jason F. Kreisberg, BS, graduate student in the UCSF Biomedical
Sciences Program; research scientist Michael P. Sherman, MD, PhD, UCSF
assistant clinical professor of medicine; and research associate Peggy S. Chin,
BA.

Co-authors from the UCLA department of microbiology, immunology and molecular
genetics include graduate student Dierdre D. Scripture-Adams, BS, and Jerome A.
Zack, PhD, professor of hematology and oncology in the UCLA department of
medicine. Also co-authors were Yael D. Korin, PhD, UCLA postdoctoral fellow in
the department of medicine, and Mario Roederer, PhD, chief of the
immunotechnology section of the Vaccine Research Center at the National
Institute of Allergy and Infectious Diseases at the National Institutes of
Health.

The work was supported by grants from the National Institutes of Health, the
UCSF Biomedical Sciences Graduate Program, the Medical Scientist Training
Program at UCSF, the California Universitywide AIDS Research Program, the
National Science Foundation, the UCSF-California AIDS Research Center, and the
J. David Gladstone Institutes.

The Gladstone Institute of Virology and Immunology is one of three research
institutes that comprise the J. David Gladstone Institutes, a private
biomedical research institution affiliated with the University of California,
San Francisco. The institutes are named for a prominent real estate developer
who died in 1971. His will created a testamentary trust that reflects his
long-standing personal interest in medical education and research.

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