AIDSWEEKLY Plus; Monday, January 18, 1999
Daniel J. DeNoon, Senior Editor

No mere side issue, the debate is about the most important and yet most mysterious phenomenon of HIV infection: the drastic depletion of T cells that heralds AIDS.

Until recently, most researchers favored the "tap-and-drain" or "raging fire" models put forward by David Ho and colleagues of Aaron Diamond AIDS Research Center, New York. This model saw HIV infection as a constant systemic battle between a horde of HIV virions and a constantly surging supply of new T cells. Ho et al. based the model on indirect measurements of circulating T-cell kinetics inferred from observations of patients treated with highly active antiretroviral therapy (HAART).

A new technique now permits direct measurement of circulating T- cell populations. And the results show that the shortened lives of T cells in people with HIV infection (the drain in Ho's model) are not compensated by increased production of new CD4(+) T cells (Ho's tap).

"Our results are inconsistent with a highly accelerated destruction of circulating CD4(+) T cells that overcomes a higher- than-normal total production rate ('open drain/open tap' model) or with isolated failure of tissue CD4 production systems (with normal survival of circulating T cells)," wrote M. Hellerstein and colleagues of the University of California, San Francisco, and colleagues.

Hellerstein et al. reported their findings in the journal Nature Medicine ("Directly Measured Kinetics of Circulating T Lymphocytes in Normal and HIV-1 Infected Humans," Nature Med, 1999;5(1):83-9).

Exactly what does happen remains unclear, pending study of lymph- node T-cell dynamics. Hellerstein et al. believe the most promising hypothesis is that HIV somehow inhibits T-cell proliferation in tissues.

The breakthrough technique used to measure human T-cell kinetics employs the stable, non-radioactive metabolite (2)H-glucose to mark cells. The marker is administered intravenously and becomes incorporated into cellular DNA during de novo nucleotide synthesis. Peripheral blood or tissue samples taken at various time points can be sorted according to cell type and assessed for isotopic enrichment by gas chromatography-mass spectrometry.

Hellerstein et al. enrolled nine healthy HIV negative subjects, seven viremic HIV positive subjects not taking antiretroviral drugs (mean CD4, 300 cells/(micro)L; range, 92-620 cells/(micro)L), and five HIV positive subjects who received 12 weeks of HAART for the first time and achieved undetectable viral loads (mean CD4 184 cells/(micro)L pretreatment, mean CD4 358 cells/(micro)L posttreatment). During the 14-day sampling period none of these three groups had any substantial changes in T-cell counts.

The healthy uninfected subjects' CD4(+) and CD8(+) T cells had respective half-lives of 87 and 77 days. Their absolute production rates were 10 CD4(+) T cells/(micro)L/day and 6 CD8(+) T cells/(micro)L/day.

The HIV infected, untreated subjects had T-cell half-lives only one third that of the healthy subjects. Their rates of CD4(+) T-cell production were no higher than those of healthy subjects (although CD8(+) production rates were about four times greater).

The HAART patients, however, had higher production rates than the healthy subjects for both CD4(+) and CD8(+) T cells. Half-lives did not increase, thus Hellerstein et al. concluded that the increase in T cell counts during HAART is the result of increased production possibly due to "disinhibition of T-cell proliferation in tissues."

The researchers suggest that a more complete picture of T-cell kinetics during HIV infection will come from further studies evaluating T cells in lymphatic tissues.

A hypothesis put forward in 1998 by William E. Paul and Zvi Grossman of the National Institutes of Health, Bethesda, Maryland, and Mark B. Feinberg of Emory University, Atlanta, Georgia, suggested that prevailing theories of HIV dynamics were oversimplistic (Grossman et al., PNAS, 1998;95:6314-9; see AIDS Weekly Plus, June 22, 1998).

Grossman et al. hypothesized that localized cells latently and chronically infected with HIV maintain virus infection and eventually lead to AIDS. Early control of HIV is not the result of equilibrium between furious production of T-cells and equally furious killing of T cells by HIV, they wrote, but simply results from the self-limiting nature of T-cell activation.

The Hellerstein et al. study was supported by grants from the NIH, the UCSF Center for AIDS Research, SpectruMedix, the UCSF/Macy's Center for Creative Therapies, and the Gladstone Institute.

The corresponding author for this study is M. Hellerstein, University of California at San Francisco, California 94110.

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