New Study Shows Shortage of Naïve T Cells in HIV-Infected Patients

STANFORD, Calif--Researchers at Stanford University Medical Centerhave found profound shortages of naïve T cells among individualsinfected with HIV. In contrast, previous studies have suggestedthat naïve T cells remain stable with the progression ofHIV disease.

"This study forces us to re-evaluate all of the experimentsthat have been done in the past 10 to 12 years on T cell functionwith cells from HIV patients," said lead investigator MarioRoederer, PhD.

He believes that the findings should also prompt a rethinkingof some proposed treatment strategies and could lead to improvedmeans of tracking disease progression in individual patients.

Naïve T cells, so called because they have not yet encounteredan antigen, are responsible for the body's initial response toinfections. Once they encounter their first foreign molecule,they turn into memory T cells, long-lived cells that protect againstsubsequent attacks.

Using a more precise identification method than in previous studies,the Stanford research team measured naïve T cells in bloodsamples from 266 HIV-infected adults with CD4 counts less than500/mL and from 44 uninfected controls.

The study found that whereas naïve cells represent about50% of all T cells in healthy adults, they make up less than 10%in adults with advanced AIDS (J Clin Invest 95:2061-2066, 1995).The shortfall of naïve cells was seen in both CD4 and CD8cells.

CD8 Function Compromised

This suggests that "AIDS is not a disease primarily of theloss of CD4 cells," said Dr. Roederer, an immunologist workingwith Stanford genetics professors Leonard A. Herzenberg and LeonoreA. Herzenberg. CD8 killer cell function is also severely compromised,he said, pointing out that the increases in CD8 cells commonlyseen early after HIV infection appear to be due primarily to increasesin memory cells.

As the naïve subsets disappear, the immune system shows aprogressive inability to mount responses to new antigens, makingpatients highly susceptible to opportunistic infections, Dr. Roederersaid. This loss will also compromise the infected person's abilityto deal with the constantly mutating virus itself.

Dr. Roederer noted that the findings call into question previousstudies of T cell function in HIV. Memory cells are the primaryproducers of certain cytokines such as IL-4, IL-10, and gammainterferon, while naïve subsets tend to produce mainly IL-2.

Therefore, previous demonstrations of functional differences incytokine production among individuals at different stages of HIVdisease, or between infected and uninfected individuals, couldmerely reflect differences in the ratio of naïve to memorycells

Dr. Leonard Herzenberg said that the results raise doubts aboutseveral treatment strategies under study, including therapeuticvaccines and some forms of gene therapy that require the activityof naïve T cells. Such approaches are almost "doomedto failure," he said, in patients whose naïve cell countsare actually quite low. The researchers suggested that any suchtherapeutic trials should be stratified with respect to naïveT cell count in addition to total CD4 count.

Dr. Roederer's coauthors, all at Stan-ford, were J. Gregson Dubs,Michael T. Anderson, Paul A. Raju, and senior authors LeonardA. Herzenberg and Leonore A. Herzenberg. The research was fundedby the National Institutes of Health.