Trends in Immunology
Opinion‘Rinse and Replace’: Boosting T Cell Turnover To Reduce HIV-1 Reservoirs
Section snippets
Chronic Immune Activation: A Mixed Blessing
A small population of CD4+ T cells containing integrated provirus, and that are able to produce replication-competent HIV-1 and remain despite effective antiretroviral therapy (ART, see Glossary), present an obstacle to curing HIV-1 infection and disease [1., 2., 3.]. By invoking the basic biology of how memory CD4+ T cells are generated and maintained, we propose a rationale for indirectly depleting the HIV-1 reservoir through a process we call ‘rinse and replace’.
The effects of chronic immune
Chronic Immune Activation Shortens the Lifespan of Latently Infected Memory CD4+ T Cells
Chronic immune activation is a hallmark of untreated HIV-1 infection [11]. During ART, the pool of provirus-containing CD4+ T cells that survive the transitional period after ART initiation is representative of the inherently long-lived population of stably infected memory CD4+ T cells that is present before ART initiation (Box 1). To determine when this pool is established during untreated disease, one study compared HIV-1 DNA p17gag sequences from patient peripheral blood mononuclear cells
The Theory: Polyclonal Activation and Feedback Control Generate a CD4+ T Cell Flux
Whereas immune responses normally generate a mixture of short- and long-lived memory CD4+ T cells, the reported results also implied shortened pre-ART lifespans of the nominally long-lived infected cells. Indeed, although cells infected relatively shortly before ART initiation appear to turn over rapidly, surviving cells regained longevity after ART initiation, proving that they were intrinsically long-lived [12,18]. This suggested that the chronicity (recurrence) of immune activation might
ART Alters the Dynamics of the HIV-1 Reservoir
Under ART, virus spread is blocked, chronic inflammation declines [63], and the activation of infected cells necessarily becomes more selective and less frequent in our model. Activation bursts are presumably also less potent because there is no or little HIV-1 replication, and therefore locally induced inflammation in lymphoid tissues cannot be amplified as much as in the untreated state. Moreover, a substantial fraction of CD4+ T cells containing intact proviruses is eliminated during the
Imitating Nature – Rinse and Replace
Our analysis suggests a novel potential strategy to reduce the infected pool of CD4+ T cells [66]. Triggering sequential waves of polyclonal T cell differentiation by inducing T cell activation while under ART might lead to gradual replacement of latently infected cells by uninfected cells (Figure 1 and Figure S2C). This conceptual approach depends on identifying stimuli that induce progenitor cells to undergo proliferation and differentiation in local activation bursts. To successfully dilute
Concluding Remarks
During untreated HIV-1 infection and upon repeated activation, extensively proliferating CD4+ T cells are progressively pushed forward and out, along their preprogrammed developmental pathways, and are replaced by newly activated cells. Consequently, integrated viral DNA is constantly washed out, strongly limiting its accumulation and diversification. Taking advantage of these controls during ART would necessitate a shift of paradigm and method – from ‘shock and kill’ to ‘rinse and replace’ –
Acknowledgments
We acknowledge the invaluable contribution by the late William E. Paul to this work. S.G.D. is supported by the amfAR Institute for HIV-1 Cure Research (amfAR 109301) and the Delaney AIDS Research Enterprise (DARE; A127966). G.B. is supported by the Russian Science Foundation (Grant 18-11-00171).
Disclaimer Statement
S.G.D. has received grant support from Gilead, Merck, and ViiV. He has consulted from AbbVie and is a member of the scientific advisory boards of BryoLogyx and Enochian Biosciences.
Glossary
- Adjuvant effect
- the local proinflammatory effect of expressed HIV-1 that is initiated when viral products bind simultaneously to the T cell receptor (TCR) and TLRs on antigen-presenting cells (APCs).
- Antiretroviral therapy (ART)
- a combination of drugs taken daily to prevent HIV-1 from infecting new cells. Different classes of antiretroviral agents act on different stages of the HIV-1 life-cycle.
- Bystander cells
- CD4+ T cells that are capable of becoming activated by a subset of antigens copresented
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Present Address: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Takeshi Kawabe, Gennady Bocharov, Martin Meier-Schellersheim, Hagit Alon, Nicolas Chomont, Zehava Grossman, Ana E. Sousa, Leonid Margolis, and Frank Maldarelli. All have full authorship. Affiliations: Takeshi Kawabe, Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan; Gennady Bocharov, Marchuk Institute of Numerical Mathematics, Russian Academy of Sciences, Moscow, Russia and Institute for Personalized Medicine, Sechenov First Moscow State Medical University, Moscow, Russia; Martin Meier-Schellersheim, Computational Systems Biology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; Hagit Alon, Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (Present address, Joy Ventures, Herzeliya, Israel); Nicolas Chomont, Department of Microbiology and Immunology, University of Montreal, Quebec, Canada; Zehava Grossman, School of Public Health, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel and HIV-1 Dynamics and Replication Program, National Cancer Institute, Frederick, MD, USA; Ana E Sousa, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal; Leonid Margolis, Section on Intercellular Interactions, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA; Frank Maldarelli, HIV-1 Dynamics and Replication Program, National Cancer Institute, Frederick, MD, USA