Disputing a Theory About AIDS Progression

By Jim Kling

Original Publication
The Scientist 15[10]:17, May 14, 2001

Evidence suggests that a decrease in CD4 ⁺ T cells is not a death sentence

For this article, Jim Kling interviewed Louis J. Picker, associate director of the Vaccine and Gene Therapy Institute at the Oregon Health Sciences University. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age.

C.J. Pitcher, C. Quittner, D.M. Peterson, M. Connors, R.A. Koup, V.C. Maino, L.J. Picker, "HIV-1-specific CD4(+) T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression," Nature Medicine, 5:518-525, May 1999. (Cited in 115 papers.)

For several years, HIV-specific CD4⁺ memory/effector T cells (CD4⁺ T cells) have been at the heart of a debate surrounding the progression of AIDS. Four years ago, a paper published in Science¹ suggested that these cells, which assist the antiviral response of HIV-specific CD8⁺ T cells, are destroyed early in the infection cycle. So it would follow, the authors argued, that if a patient's CD4⁺ T cell count remained high, his prognosis would be good (and he would perhaps escape AIDS altogether). But if the cell count were low or nonexistent, clinical AIDS was probably just around the corner. The authors also believed that maintaining the CD4⁺ T cell count could hold the key to combating the disease.

That argument did not sit well with Louis J. Picker, associate director of the Vaccine and Gene Therapy Institute at Oregon Health Sciences University in Portland. "The proliferation studies [used to measure the presence of CD4⁺ T cells] have a six-day readout time," he says. "It's been shown that you're measuring the overall ability of T cells to proliferate under those conditions." In other words, cells that don't thrive in vitro might die in culture. At the experiment's end, those cells would be under-represented, leading researchers to conclude mistakenly that little or no CD4⁺ T cells were present in the sample.²

Picker and his colleagues got to work trying to "assess the hypothesis that HIV-specific memory CD4+ T cells were absent in active HIV infection, either because they developed but were killed off or perhaps because they never developed," he says. "The absence of these cells was being touted as the 'missing link.' That is, the defect responsible for why the immune system doesn't control HIV infection. Our data suggests it is more complicated than that."

Picker has made a career of developing flow cytometry methods, and he applied his work, already completed on other viral systems, to HIV. He and his colleagues spent five years perfecting the conditions that would provide consistent T cell activation. Once in this state, these cells produce cytokines on their surfaces that can detect and sort the cells through flow cytometry. Most importantly, the team could carry out the flow cytometry assay within six hours of applying the cells to the culture medium. This way, the cells would not go through any replication cycles and the results would not be skewed.

Picker began with patients who were long-term nonprogressors--HIV+ individuals whose overall T cell counts had remained steady and showed no sign of clinical AIDS. As already observed by other researchers, Picker found that these patients maintained healthy HIV-specific CD4⁺ T cell counts. He then turned to patients who were not on antiretroviral therapy and whose disease was progressing. As indicated in this Hot Paper, Picker and colleagues found that these patients had surviving CD4⁺ T cell populations, albeit at low levels. Previous observations had indicated otherwise.

"There was no clear-cut association between viral load and the [numbers] of these cells," says Picker, suggesting that HIV-specific CD4⁺ T cell levels are not an accurate marker of disease progression, as the authors of the Science paper had hypothesized. Picker comments that his work has improved the methodology available to study immune system process. This in vitro and flow cytometry assay "has revolutionized the way we look at T cell memory in humans. More and more studies are using this approach to quantify vaccine responses."

The researchers continue to investigate the role of HIV-specific CD4+ cells in controlling infection, and whether they contribute to infection. HIV-specific CD4+ T cells are targets of the virus, says Picker, and it is possible that having more of them just gives the virus more activated T cells to attack. "We have moved to a nonhuman primate model (SIV) to assess this question...; this model allows us to look at very early events during infection."

References

1. E.S. Rosenberg et al., "Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia," Science, 278:1447-50, 1997.

2. L.J. Picker and V.C. Maino, "The CD4+ T cell response to HIV-1,"

Current Opinion in Immunology, 12:381-6, 2000.