Trends in Pharmacological Sciences
Research FocusHIV-1-induced depletion of CD4+ T cells in the gut: mechanism and therapeutic implications
Section snippets
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.
References (25)
HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure
Cell
(1990)Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency
New Engl. J. Med.
(1981)Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS
Science
(1984)Viral dynamics in human immunodeficiency virus type 1 infection
Nature
(1995)Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection
Nature
(1995)Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection
Nature
(1997)Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes
Nat. Med.
(1995)Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage
J. Infect. Dis.
(1999)Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection
Science
(1998)Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract
J. Exp. Med.
(2004)