HIV infects naive T cells leading to depletion

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 behaviour 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 labelled 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.