Does Cytolysis by CD8+ T Cells Drive Immune Escape in HIV Infection?

Self Cite

dEarly studies of HIV infection dynamics suggested that virus-producing HIV-infected cells had an average half-life of approximately 1 day. However, whether this average behavior is reflective of the dynamics of individual infected cells is unclear. Here, we use HIV-enhanced green fluorescent protein (EGFP) constructs and flow cytometry sorting to explore the dynamics of cell infection, viral protein production, and cell death in vitro. By following the numbers of productively infected cells expressing EGFP over time, we show that infected cell death slows down over time. Although infected cell death in vivo could be very different, our results suggest that the constant decay of cell numbers observed in vivo during antiretroviral treatment could reflect a balance of cell death and delayed viral protein production. We observe no correlation between viral protein production and death rate of productively infected cells, showing that viral protein production is not likely to be the sole determinant of the death of HIV-infected cells. Finally, we show that all observed features can be reproduced by a simple model in which infected cells have broad distributions of productive life spans, times to start viral protein production, and viral protein production rates. This broad spectrum of the level and timing of viral protein production provides new insights into the behavior and characteristics of HIV-infected cells.

Section: Discussionsupporting

confidence: 71%

Intracellular Dynamics of HIV Infection

Petravic

Ellenberg

Chan

et al. 2014

Self Cite

“…Such a nonlytic T cell response should be able to select for viral escape. Recent studies suggest that nonlytic control of virus replication may be the major mechanism of suppression of SIV replication in monkeys (13,53,98). Importantly, this model predicts a slower accumulation of the escape variant if the total magnitude of the CD8 ϩ response is high (Fig.…”

Section: Downloaded Frommentioning

confidence: 99%

Fitness Costs and Diversity of the Cytotoxic T Lymphocyte (CTL) Response Determine the Rate of CTL Escape during Acute and Chronic Phases of HIV Infection

Ganusov

Goonetilleke

Liu

et al. 2011

149

269

HIV-1 often evades cytotoxic T cell (CTL) responses by generating variants that are not recognized by CTLs.We used single-genome amplification and sequencing of complete HIV genomes to identify longitudinal changes in the transmitted/founder virus from the establishment of infection to the viral set point at 1 year after the infection. We found that the rate of viral escape from CTL responses in a given patient decreases dramatically from acute infection to the viral set point. Using a novel mathematical model that tracks the dynamics of viral escape at multiple epitopes, we show that a number of factors could potentially contribute to a slower escape in the chronic phase of infection, such as a decreased magnitude of epitope-specific CTL responses, an increased fitness cost of escape mutations, or an increased diversity of the CTL response. In the model, an increase in the number of epitope-specific CTL responses can reduce the rate of viral escape from a given epitope-specific CTL response, particularly if CD8 ؉ T cells compete for killing of infected cells or control virus replication nonlytically. Our mathematical framework of viral escape from multiple CTL responses can be used to predict the breadth and magnitude of HIV-specific CTL responses that need to be induced by vaccination to reduce (or even prevent) viral escape following HIV infection.

“…Studies conducted by us and others have shown that depletion of CD8 ϩ lymphocytes in SIV-infected RMs followed by ART treatment did not alter the life span of productively SIV-infected cells or impact viral decay kinetics compared to undepleted animals (26,27). In addition, decay rates of wild-type and escape mutant virus were found to be similar during the acute phase of simian-human immunodeficiency virus (SHIV) infection of macaques (28). Suppression of HIV replication by CD8 ϩ T cells via noncytolytic mechanisms that inhibit virus transcription was first observed by Levy and colleagues in 1986 (29,30), although the molecular mechanisms underlying this antiviral activity have remained elusive (31)(32)(33).…”

mentioning

confidence: 75%

Transcriptional Profiling of Experimental CD8⁺Lymphocyte Depletion in Rhesus Macaques Infected with Simian Immunodeficiency Virus SIVmac239

Bosinger

Jochems

Folkner

et al. 2013

c CD8 ؉ T cells inhibit virus replication in SIV-infected rhesus macaques. However, it is unclear to what extent the viral suppression mediated by CD8؉ T cells reflects direct killing of infected cells as opposed to indirect, noncytolytic mechanisms. In this study, we used functional genomics to investigate noncytolytic mechanisms of in vivo viral suppression mediated by CD8؉ lymphocytes. Eight chronically SIVmac239-infected rhesus macaques underwent CD8؉ lymphocyte depletion, and RNA from whole blood was obtained prior to depletion, during the nadir of CD8 ؉ cell depletion, and after CD8 ؉ lymphocyte numbers had rebounded. We observed significant downregulation of the expression of genes encoding factors that can suppress SIV replication, including the CCR5-binding chemokine CCL5/RANTES and CCL4 and several members of the tripartite motif-containing (TRIM) family. Surprisingly, we also noted a strong, widespread downregulation of ␣-and -defensins with anti-HIV activity, which are not expressed by CD8 ؉ T cells. After cessation of depleting antibody treatment, we observed induction of a transcriptional signature indicative of B lymphocyte activation. Validation experiments demonstrated that animals during this period had elevated levels of B cells coupled with higher expression of the proliferative marker Ki67, indicating that CD8 ؉ depletion triggered a potent expansion of B cell numbers. Collectively, these data identify antiviral pathways perturbed by in vivo CD8؉ T cell depletion that may contribute to noncytolytic control of SIV replication.