A study published in the new issue of the journal Cell reports that the entry of HIV into CD4 T cells can cause their depletion in the absence of productive infection. The lead author is Gilad Doitsh from Warner Greene’s group at the Gladstone Institute of Virology and Immunology in San Francisco. As happens quite often, the mainstream media reporting on the paper has not been particularly accurate; the general narrative is that the mechanism of HIV-induced CD4 T cell death was a mystery that is now solved. This is not really true; there are several well-described ways in which HIV infection can cause cells to die (such as apoptosis mediated by the protein Vpr) and the increased levels of immune activation in untreated HIV infection also leads to the activation-induced death of not only uninfected CD4 T cells but CD8 T cells, B cells and other immune cell types (including dendritic cells). Furthermore, the mechanism described in the new study primarily relates to HIV viruses that enter CD4 T cells via the CXCR4 co-receptor (aka X4-tropic viruses), and roughly half of all people with HIV infection progress to AIDS without ever showing evidence of X4-tropic virus (it is particularly rare in individuals with subtype C HIV infection). Most HIV isolates enter cells via the CCR5 co-receptor.
That being said, research has documented a consistent association between the emergence of X4-tropic HIV late in the course of infection and rapid CD4 T cell loss. Additionally, hybrids of simian immunodeficiency viruses and X4-tropic HIV (such as SHIV89.6p) cause a rapid and sustained loss of CD4 T cells in macaques. The new paper in Cell may well have revealed the underlying basis for these phenomena.
The study uses a model system in which lymphoid tissue from the tonsils is cultured and maintained in the laboratory. Previous studies involving the same system have shown that the introduction of X4-tropic HIV isolates causes the almost complete depletion of CD4 T cells from the culture, even though only a minority (~5%) can be shown to be productively infected. This “bystander” effect involves non-activated resting CD4 T cells that are typically not able to support productive HIV infection.
Gilad Doitsh and colleagues employ a variety of antiretroviral drugs to probe how this indirect killing of CD4 T cells occurs, revealing that the entry of HIV is required but integration of HIV DNA into the cell genome is not. Ultimately they show that HIV enters these CD4 T cells and reverse transcription is initiated but not completed, leading to the accumulation of HIV genetic material which then triggers a cellular defense pathway involving the production of mediators of inflammation and cell death. Although the majority of the work involved tonsil tissue, additional experiments were conducted with spleen samples in order to confirm that the findings were also applicable to other lymphoid sites.
Although the authors write in their abstract that the mechanism they have identified “centrally contributes to the immunopathogenic effects of HIV,” this conclusion is perhaps debatable given the limitation to X4-tropic virus. Although presumably R5-tropic HIV is capable of provoking a similar cellular response, the CCR5 co-receptor is almost exclusively expressed on activated CD4 T cells, which--unlike resting cells--are permissive for productive infection. This issue is not discussed in the paper and none of the press articles I can find mention the X4/R5 distinction. The fact that R5-tropic HIV alone can cause disease suggests that while the newly-identified mechanism may accelerate progression, it is not necessarily central to pathogenesis.
Cell, Volume 143, Issue 5, 789-801, 24 November 2010
Gilad Doitsh, Marielle Cavrois, Kara G. Lassen, Orlando Zepeda, Zhiyuan Yang, Mario L. Santiago, Andrew M. Hebbeler, Warner C. Greene
Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, CA 94158, USA Department of Medicine, University of California, San Francisco, CA 94143, USA Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA Corresponding author Present address: University of Colorado, Denver, Aurora, CO 80045, USA These authors contributed equally to this work
The mechanism by which CD4 T cells are depleted in HIV-infected hosts remains poorly understood. In ex vivo cultures of human tonsil tissue, CD4 T cells undergo a pronounced cytopathic response following HIV infection. Strikingly, >95% of these dying cells are not productively infected but instead correspond to bystander cells. We now show that the death of these “bystander” cells involves abortive HIV infection. Inhibitors blocking HIV entry or early steps of reverse transcription prevent CD4 T cell death while inhibition of later events in the viral life cycle does not. We demonstrate that the nonpermissive state exhibited by the majority of resting CD4 tonsil T cells leads to accumulation of incomplete reverse transcripts. These cytoplasmic nucleic acids activate a host defense program that elicits a coordinated proapoptotic and proinflammatory response involving caspase-3 and caspase-1 activation. While this response likely evolved to protect the host, it centrally contributes to the immunopathogenic effects of HIV.