AIDSWEEKLY Plus, Monday, 3 November 1997
Daniel J. DeNoon, Senior Editor

Slow but steady T-cell increases in people receiving effective anti-HIV therapy may mean that their immune systems eventually will recover.

While it is too soon to know the extent to which competent immune function can be restored to people with HIV disease, available data are promising for those who begin highly active antiretroviral therapy (HAART) while their CD4 T-cell counts are still above 100 cells/(micro)L.

"Data suggest that there can really be repopulation of naive T cells that might have a full expression of the T-cell repertoire and might result in effective immune reconstitution, eventually," said Donald E. Mosier of The Scripps Research Institute, La Jolla, California. "However, it is far too soon to be comfortable with that conclusion."

Mosier presented a state-of-the-art lecture on T-cell dynamics during HIV infection to the American Society for Microbiology's 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 28 to October 1, 1997, in Toronto, Ontario, Canada.

Mosier noted that after beginning HAART, patients with an initial CD4 count >100 cells/(micro)L have a two-phase increase in CD4 cell counts. An initial large increase, he said, is due to recirculation of memory T cells trapped in lymphoid tissues.

But about a month later, a slow and steady increase of about 10(8) CD4 T cells per day begins, resulting in a CD4 count increase of 1 to 2 cells/(micro)L per week. Most of these cells represent expansion of existing memory cells, but some appear to be new, naive T cells.

"It will be very important to see whether this can be sustained and whether the holes in the T-cell repertoire can eventually be filled by new cells with a normal T-cell repertoire and the ability to recognize the range of opportunistic infections to which this patient population is exposed," Mosier said.

However, Mosier noted that the post-therapy CD4 T-cell replacement rate is a very small fraction of the total T-cell pool in an individual. Estimates put the total T-cell pool at 3x10(11) cells. Thus, the daily replacement rate would be 0.00033 percent of the total.

Mosier observed that T-cell turnover is an ambiguous measurement and that the lifespan of a T-cell can end by two quite different events: division or death.

"Most of our data from normal animals suggest that division is the limiting factor in lifespan; that is, division is much more frequent than death as an endpoint for a T-cell," he said. "But in a patient who is infected with HIV quite the opposite is true for CD4 T cells because death is much more likely as an endpoint than cell division. This complicates the translation of data from normal animal models and humans to the infected patient."

The two major forms of T cells are naive cells that have not previously encountered antigen, and memory cells that have been stimulated by antigen and have reverted to a resting stage. The two types can be distinguished by the isoform of the CD45 homing receptor on the surface of the cells: naive cells carry small amounts of the RA isoform (and high levels of the CD62L or L-selectin molecule) and memory cells carry large amounts of the RO isoform (and low levels of CD26L).

Complicating the issue, however, is that between these two major T-cell types is the intermediary activated T-cell. Most T cells activated by antigen normally are eliminated by programmed cell death, or apoptosis, and only a revert from the activated state to become long-term memory cells.

New findings show that naive T cells express the CXCR4 chemokine receptor used for cell entry by T-cell-tropic (T- tropic) syncytium-inducing (SI) HIV-1 strains while memory T cells express the CCR5 chemokine receptor used for cell entry by macrophage-tropic (M-tropic) non-syncytium-inducing (NSI) HIV-1 strains.

"This makes these two populations different in terms of susceptibility to virus infection, both in terms of the type of virus they're infected by and also by the fact that while the virus can enter naive resting T cells. It doesn't replicate because the cell is resting and doesn't support the virus replication machinery so the virus is really replication negative in these cells although a few resting cells apparently can allow viral integration and persistence as a viral integrated form," Mosier said. "In contrast, memory T cells are permissive for virus replication, although we have to distinguish that active T cells are highly permissive for viral replication whereas resting long-term memory cells seem to be somewhat less permissive."

These findings reveal a new paradox for HIV infection: while activated T cells bearing the CD45RO phenotype are the primary targets for HIV, the relative proportion of CD45RO cells goes up instead of down. This paradox is made even more puzzling by the observation that exposure to HIV envelope proteins can induce apoptosis in memory cells not infected with HIV.

"It's really CD45RA naive T cells that disappear, Mosier said. "Despite the fact that RA cells are not good targets for infection, they're the ones that seem to suffer the most during HIV infection."

Mosier offered two explanations for this phenomenon:

* Regeneration of CD45RO T cells from peripheral expansion comes close to equalling the death rate due to HIV infection.

* Intrathymic HIV infection abolishes production of naive CD4 T cells.

Whatever the cause of HIV induced imbalances in the T-cell repertoire, the main concern for patients is regeneration of T cells after HIV is brought under control.

Mosier suggested that there may be several sources of CD4 replacement:

* Thymus regeneration of new naive T cells. "We thought the thymus had limited regeneration capacity in adults that was further impaired by HIV infection," Mosier said. "But it remains to be shown that there is no thymic regeneration." He noted that in HIV infected SCID mice with fetal thymic implants, combination therapy allows the thymus to regenerate.

* Reentry of sequestered cells into circulation. While this phenomenon is the main cause of the initial rise in CD4 cells after therapy, it remains unclear whether it is the only cause.

* Reversal of cell death. "If there is a high rate of cell death during HIV infection and you substantially reduce the rate you will see a compensatory increase in CD4 cells," Mosier said.

* Peripheral expansion of T cells. Initiated by the overstimulation of T cells characteristic of HIV infection, this phenomenon may continue even after treatment.

Data from patients with more time on effective antiretroviral therapy and more data on T-cell function in treated patients will be needed to confirm these preliminary observations, Mosier warned.

"Very little is known about the function of regained T cells," he said. "The small amount of data available is optimistic, but much more data are needed before we can say that immune function is reconstituted."

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