Residual Viral Replication during Antiretroviral Therapy Boosts Human Immunodeficiency Virus Type 1-Specific CD8<sup>+</sup>T-Cell Responses in Subjects Treated Early after Infection

Ortiz, Gabriel M.; Hu, Juguang; Goldwitz, Joshua A.; Chandwani, Rohit; Larsson, Marie; Bhardwaj, Nina; Bonhoeffer, Sebastian; Ramratnam, Bharat; Zhang, Linqi; Markowitz, Martin; Nixon, Douglas F.

doi:10.1128/jvi.76.1.411-415.2002

Cited by 25 publications

(19 citation statements)

References 46 publications

(27 reference statements)

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“…The reason is almost certainly that HIV infection results in the depletion of specific immune cells, leaving not enough cells to react. ** However, the dynamics of cytotoxic T lymphocyte responses observed during treatment (27) support patterns observed in our model. Among subjects treated relatively early, the average level of HIV-specific CD8 T cell responses during therapy was higher in patients who showed two or more viremic episodes per year compared with patients in whom drug therapy suppressed HIV replication more efficiently.…”

Section: Application and Discussionsupporting

confidence: 86%

Boosting immunity by antiviral drug therapy: A simple relationship among timing, efficacy, and success

Komarova

Barnes²,

Klenerman³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Drug therapies against persistent human infections such as hepatitis C virus, hepatitis B virus, and HIV fail to consistently eradicate the infection from the host. Hence, recent emphasis has shifted to the study of antiviral therapy aimed at boosting specific immune responses. It was argued that structured therapy interruptions were required to achieve this, because such regimes have shown promising results in early HIV infection. Using mathematical models, we show that, contrary to this notion, a single phase of drug therapy can result in the establishment of sustained immunity. We present a simple relationship between timing of therapy and efficacy of the drugs required for success. In the presence of strong viral suppression, we show that therapy should be stopped relatively early, and that a longer duration of treatment leads to failure. On the other hand, in the presence of weaker viral suppression, stopping treatment too early is detrimental, and therapy has to be continued beyond a time threshold. We discuss our modeling results primarily in the context of HCV therapy during chronic infection. Although the therapy regimes explored here also have implications for HIV, virus-mediated destruction of specific immune cells renders success unlikely during the chronic phase of the infection.

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Section: Application and Discussionsupporting

confidence: 86%

Boosting immunity by antiviral drug therapy: A simple relationship among timing, efficacy, and success

Komarova

Barnes²,

Klenerman³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…However, other studies report the opposite findings, where blood HIV-specific responses increase after the initiation of HAART (2,46). These discrepancies could be attributable to variations in both the time of treatment initiation and the degree to which viral replication is suppressed (44).…”

contrasting

confidence: 38%

Persistence of Genital Tract T Cell Responses in HIV-Infected Women on Highly Active Antiretroviral Therapy

Mkhize¹,

Gumbi²,

Liebenberg³

et al. 2010

J Virol

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Initiation of highly active antiretroviral therapy (HAART) for HIV-infected individuals is associated with control of viremia, improved CD4 counts, and declining systemic HIV-specific immune responses. While HAART effectively reduces plasma viremia, it remains unclear how effectively antiretroviral drugs reach mucosal surfaces, such as those of the genital tract. The aim of this study was to determine the effect of HAART on genital tract CD4 T cell reconstitution, HIV shedding, and HIV-specific T cell responses. Cervical cytobrush and blood specimens were obtained from 35 HIV-infected, HAART-naïve women and 27 women on HAART in order to investigate HIV Gag-specific T cell responses by intracellular gamma interferon (IFN-␥) staining. Interleukin 1␤ (IL-1␤), IL-6, and IL-8 concentrations were measured by enzyme-linked immunosorbent assays (ELISA). We show that for HIV-infected women, HAART is associated with significantly improved CD4 T cell counts both in blood and at the cervix. While HAART effectively suppressed both blood and cervical viremia, HIV-specific CD8 T cell responses in blood were lost, while those at the cervix were preserved.

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“…However, some latent viruses will provide effective T-cell boosts during periods of reactivation and maintain a large population of functional virus-specific T cells, as seen for EBV (18). This situation might also arise during highly active antiretroviral therapy or structured treatment interruptions of highly active antiretroviral therapy for HIV patients, since occasional viremic episodes can be associated with increased HIV-specific CD8 Tcell frequencies (57). The benefit of low-level viral persistence or periodic viral reactivation for maintaining elevated T-cell numbers, however, is likely to be determined by the level of epitope presentation in vivo and/or the frequency of T-cell encounter with antigen.…”

Section: Discussionmentioning

confidence: 99%

Viral Persistence Alters CD8 T-Cell Immunodominance and Tissue Distribution and Results in Distinct Stages of Functional Impairment

Wherry

Blattman

Murali‐Krishna

et al. 2003

J Virol

1,378

1,664

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Chronic viral infections often result in ineffective CD8 T-cell responses due to functional exhaustion or physical deletion of virus-specific T cells. However, how persisting virus impacts various CD8 T-cell effector functions and influences other aspects of CD8 T-cell dynamics, such as immunodominance and tissue distribution, remains largely unknown. Using different strains of lymphocytic choriomeningitis virus (LCMV), we compared responses to the same CD8 T-cell epitopes during acute or chronic infection. Persistent infection led to a disruption of the normal immunodominance hierarchy of CD8 T-cell responses seen following acute infection and dramatically altered the tissue distribution of LCMV-specific CD8 T cells in lymphoid and nonlymphoid tissues. Most importantly, CD8 T-cell functional impairment occurred in a hierarchical fashion in chronically infected mice. Production of interleukin 2 and the ability to lyse target cells in vitro were the first functions compromised, followed by the ability to make tumor necrosis factor alpha, while gamma interferon production was most resistant to functional exhaustion. Antigen appeared to be the driving force for this loss of function, since a strong correlation existed between the viral load and the level of exhaustion. Further, epitopes presented at higher levels in vivo resulted in physical deletion, while those presented at lower levels induced functional exhaustion. A model is proposed in which antigen levels drive the hierarchical loss of different CD8 T-cell effector functions during chronic infection, leading to distinct stages of functional impairment and eventually to physical deletion of virus-specific T cells. These results have implications for the study of human chronic infections, where similar T-cell deletion and functional dysregulation has been observed.Considerable evidence suggests that an effective CD8 T-cell response can control or eradicate viral infections. CD8 T cells appear to be particularly important in the immune response to chronic infections and in the long-term control of latent and reactivating viruses (2, 26). Indeed, potent human immunodeficiency virus (HIV)-specific CD8 T-cell responses correlate with acute viral control and long-term nonprogression (16,42,55,56,61,66). Further, rhesus macaques infected with simian immunodeficiency virus (SIV) show significantly higher viral loads if CD8 T cells are eliminated by antibody-mediated depletion (38). Evidence also suggests that CD8 T cells are important for the acute phase as well as long-term control of other persistent viruses, such as Epstein-Barr virus (EBV), cytomegalovirus, hepatitis B virus (HBV), and hepatitis C virus (HCV) (18,24,63,83). However, in many patients CD8 T cells fail to contain viral replication, particularly during HIV, HBV, and HCV infections. Recent studies suggest that functional impairment (exhaustion) and/or physical deletion of CD8 T cells can accompany ineffective viral control (44, 85). However, the impact of chronic viral infection on the induction and m...

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Residual Viral Replication during Antiretroviral Therapy Boosts Human Immunodeficiency Virus Type 1-Specific CD8⁺T-Cell Responses in Subjects Treated Early after Infection

Cited by 25 publications

References 46 publications

Boosting immunity by antiviral drug therapy: A simple relationship among timing, efficacy, and success

Boosting immunity by antiviral drug therapy: A simple relationship among timing, efficacy, and success

Persistence of Genital Tract T Cell Responses in HIV-Infected Women on Highly Active Antiretroviral Therapy

Viral Persistence Alters CD8 T-Cell Immunodominance and Tissue Distribution and Results in Distinct Stages of Functional Impairment

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Residual Viral Replication during Antiretroviral Therapy Boosts Human Immunodeficiency Virus Type 1-Specific CD8+T-Cell Responses in Subjects Treated Early after Infection

Cited by 25 publications

References 46 publications

Boosting immunity by antiviral drug therapy: A simple relationship among timing, efficacy, and success

Boosting immunity by antiviral drug therapy: A simple relationship among timing, efficacy, and success

Persistence of Genital Tract T Cell Responses in HIV-Infected Women on Highly Active Antiretroviral Therapy

Viral Persistence Alters CD8 T-Cell Immunodominance and Tissue Distribution and Results in Distinct Stages of Functional Impairment

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Product

Resources

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Residual Viral Replication during Antiretroviral Therapy Boosts Human Immunodeficiency Virus Type 1-Specific CD8⁺T-Cell Responses in Subjects Treated Early after Infection