AIDSWEEKLY Plus, Monday, 14 April 1997
Daniel J. DeNoon, Senior Editor

Strategies to inhibit HIV induced programmed cell death or apoptosis may backfire.

New studies show that apoptosis may actually be a beneficial mechanism that limits the spread of HIV. Experimental inhibition of apoptosis actually enhanced in vitro and ex vivo HIV replication.

University of Michigan researchers Arul M. Chinnaiyan, Gary J. Nabel, and colleagues reported the findings in the journal Nature Medicine ("The Inhibition of Pro-Apoptotic ICE- Like Proteases Enhances HIV Replication," Nat Med, 1997;3(3):333-40).

"The results of this study suggest that inhibition of apoptosis may potentiate viral replication and that therapeutic interventions designed to block apoptosis may be potentially detrimental to the HIV infected individual and, if undertaken at all, should be done in combination with continuous potent antiretroviral agents and careful, frequent monitoring of viral load," Chinnaiyan et al. wrote.

Apoptosis is a natural function involving the self destruction of cells no longer needed by the body. The process is crucial to normal development and homeostasis. This process is disrupted in a variety of human diseases.

Several research groups have noted that peripheral blood mononuclear cells (PBMCs) and CD4(+) T lymphocytes from people with HIV infection undergo rapid apoptosis in vitro. Many of these researchers have suggested that inhibition of apoptosis would slow or prevent T-cell loss in such patients.

"Many diverse agents have been shown to abrogate HIV induced apoptosis in vitro, including protease inhibitors, retinoic acid, soluble Fas/APO-1, antioxidants, cyclosporin A, FK506, viral gene products, interleukin 12, and glucocorticoids," Chinnaiyan et al. noted. "However, it is unclear whether inhibition of apoptosis would be beneficial to the HIV infected individual since activation of an endogenous cell-suicide program may serve as a host defense mechanism against viral proliferation."

Chinnaiyan et al. first experimented with CD4(+) CEM T- leukemia cells, which when exposed to HIV-1 undergo apoptosis. Apoptosis in these cells is mediated by interleukin-1(beta)- converting enzyme (ICE) proteases. The researchers therefore exposed the cells to the broad-spectrum ICE-family inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD- fmk), a known inhibitor of apoptosis.

"We observed a surprising and profound increase in the RT [reverse transcriptase] levels of culture supernatants derived from z-VAD-fmk-treated CEM cells," the researchers found.

Another ICE inhibitor had a similar effect.

The experiment was repeated during acute infection of primary cells with HIV. RT production was three times greater, and more prolonged, in the presence of the ICE inhibitor. Similar effects were seen with both syncytium- inducing and non-syncytium-inducing HIV strains.

Finally, Chinnaiyan et al. incubated PBMCs from five asymptomatic HIV infected donors with z-VAD-fmk (no new virus was added to these cultures). In the cells from three of the five donors, the ICE inhibitor stimulated endogenous viral replication.

"Differences in viral load, quasispecies, tropisms, and inhibitory factors may explain why z-VAD-fmk did not stimulate endogenous viral replication in cells from all HIV infected individuals; however, it is reasonable to speculate that inhibiting apoptosis in tissues highly infected with HIV (such as the lymphoid organs) would lead to an even more pronounced enhancement of viral replication," they wrote.

The results of these studies are contrast to reports that anti-apoptotic glucocorticoids do not significantly increase HIV replication in PBMCs (Lu et al., AIDS, 1995;9(1):35-42; Thali et al., Nature, 1994;372:363-5; and Andrieu et al., J Infect Dis, 1995;171(3):523-30).

"It is thus possible that other anti-apoptotic agents that act by alternative mechanisms to promote cell death may exert different effects on HIV replication, depending on their mode and specificity of action," Chinnaiyan et al. suggested.

In fact, the authors noted the proposal put forward by NIH researchers Guiseppe Pantaleo and Anthony S. Fauci (Nat Med, 1995;1:118-20): that there are two components of apoptosis in HIV infection. One might be normal, acting to eliminate effector cells, and the other might be detrimental, reflecting abnormal cell signals.

But whatever the specific mechanism, Chinnaiyan et al. advised extreme caution in interfering with apoptosis in patients.

An interesting spin-off from the current study is the potential application of the finding that z-VAD-fmk amplifies HIV replication in PBMCs from infected donors.

"z-VAD-fmk ... may serve as a valuable means of isolating previously unrescuable virus in blood and tissue samples being analyzed for diagnostic purposes or of studying disease pathogenesis in asymptomatic individuals," Chinnaiyan et al. suggested.

The corresponding author for this study is Gary J. Nabel, Howard Hughes Medical Institute and Departments of Internal Medicine and Biological Chemistry, University of Michigan Medical Center, 1150 West Medical Center Drive, 4520 MSRBI, Ann Arbor, Michigan 48109-0650.

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