Research Focus
HIV-1-induced depletion of CD4+ T cells in the gut: mechanism and therapeutic implications

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The mechanism of CD4+ T-cell depletion remains a central unresolved issue in AIDS research. Recent studies have examined the massive depletion of CD4+ T cells observed in macaque models of acute HIV infection. A key question is whether the observed CD4+ T-cell death is due to direct consequences of viral infection and to indirect mechanisms including increased expression of mediators of T-cell apoptosis. The therapeutic implications of the early CD4+ T-cell loss are discussed.

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CD4+ T-cell depletion in the gut

Even in the earliest description of the immunodeficiency disease now termed AIDS, it was noted that affected patients lacked CD4+ T cells [1]. Almost 25 years later, it remains unclear how this key cellular population is lost. HIV-1 selectively infects and kills CD4+ T cells in vitro, suggesting that direct virus-induced death of infected cells contributes to CD4 depletion [2]. Pioneering studies of HIV-1 dynamics confirmed that most infected cells die quickly in vivo 3, 4. However, during the

Mechanisms of CD4+ T-cell depletion

Although activated memory CD4+ T cells in the lamina propria of the intestine are a major target for viral replication and CD4 depletion early in acute infection, the mechanism of depletion remains controversial. Mattapalli et al. suggest that most of the CD4+ T-cell loss results from direct infection of a high fraction of the total memory cell pool (Figure 2). Interestingly, the infection rate they measure with a PCR assay for SIV Gag DNA is much higher than the rate arrived at by Li et al.

Therapeutic implications

These findings have prompted interest in therapeutic interventions that would prevent this early loss of CD4+ T cells. All mechanisms for CD4 depletion, even indirect mechanisms, depend on viral replication. Halting replication with combination antiretroviral therapy generally reverses the loss of CD4+ T cells and enables substantial immune reconstitution [22], but whether this is true for the GALT remains controversial 9, 23. Current therapeutic guidelines do not make firm recommendations

Acknowledgements

This work was supported by NIH grants AI43222 and AI51178, a grant from the Doris Duke Charitable Foundation, and the Howard Hughes Medical Institute.

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