Kinetics of Response in Lymphoid Tissues to Antiretroviral Therapy of HIV-1 Infection

Cavert, Winston; Notermans, Daan W.; Staskus, Katherine; Wietgrefe, Stephen W.; Zupancic, Mary; Gebhard, Kristin; Henry, Keith; Zhang, Zhi‐Qiang; Mills, Roger; McDade, Hugh; Goudsmit, Jaap; Danner, Sven A.; Haase, Ashley T.

doi:10.1126/science.276.5314.960

Cited by 542 publications

(341 citation statements)

References 16 publications

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“…HAART dramatically reduces the amount of viral RNA detected on FDCs (34,35). However, even with HAART, some virus remains after prolonged therapy, and levels below 10,000 copies of viral RNA per gram tissue may not be detected (11,34,35).…”

Section: Figurementioning

confidence: 99%

“…The rate of virus decay from FDCs in patients receiving HAART is biphasic: the first phase decays with a t 1/2 of 1.7 days, and the second phase with a t 1/2 of 14 days (34). These data are in apparent contradiction to the longer decay periods observed in our murine study, although Hlavacek et al (37), using a stochastic model of decay, calculated that with a beginning virus load of 10 11 copies of RNA, virions could still be expected for as long as 10 yr. We hypothesize that differences between the Cavert study and ours may be related to analysis of the FDC network under very different conditions of FDC-virus density.…”

Section: Figurementioning

confidence: 99%

“…In humans, the FDC reservoir of HIV is estimated at 1.5 ϫ 10 8 copies of viral RNA per gram of lymphoid tissue (11,34). HAART dramatically reduces the amount of viral RNA detected on FDCs (34,35).…”

Section: Figurementioning

confidence: 99%

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Persistence of Infectious HIV on Follicular Dendritic Cells

Smith¹,

Gartner

Liu

et al. 2001

The Journal of Immunology

173

151

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Follicular dendritic cells (FDCs) trap Ags and retain them in their native state for many months. Shortly after infection, HIV particles are trapped on FDCs and can be observed until the follicular network is destroyed. We sought to determine whether FDCs could maintain trapped virus in an infectious state for long periods of time. Because virus replication would replenish the HIV reservoir and thus falsely prolong recovery of infectious virus, we used a nonpermissive murine model to examine maintenance of HIV infectivity in vivo. We also examined human FDCs in vitro to determine whether they could maintain HIV infectivity. FDC-trapped virus remained infectious in vivo at all time points examined over a 9-mo period. Remarkably, as few as 100 FDCs were sufficient to transmit infection throughout the 9-mo period. Human FDCs maintained HIV infectivity for at least 25 days in vitro, whereas virus without FDCs lost infectivity after only a few days. These data indicate that HIV retained on FDCs can be long lived even in the absence of viral replication and suggest that FDCs stabilize and protect HIV, thus providing a long-term reservoir of infectious virus. These trapped stores of HIV may be replenished with replicating virus that persists even under highly active antiretroviral therapy and would likely be capable of causing infection on cessation of drug therapy.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Persistence of Infectious HIV on Follicular Dendritic Cells

Smith¹,

Gartner

Liu

et al. 2001

The Journal of Immunology

173

151

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“…Treatment with highly active antiretroviral therapy (HAART), combining HIV protease inhibitors (PI) and reverse transcriptase inhibitors (RTI), can suppress HIV replication both in the circulation and in lymphoid tissues and improve both CD4 1 T cell count and function [1]. However, in spite of intense investigation, the mechanisms underlying HAART-induced immune reconstitution remain to be fully characterized.…”

Section: Introductionmentioning

confidence: 99%

T cell responses to highly active antiretroviral therapy defined by chemokine receptors expression, cytokine production, T cell receptor repertoire and anti-HIV T-lymphocyte activity

Giovannetti

Pierdominici

Mazzetta

et al. 2001

Clinical and Experimental Immunology

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SUMMARYThe immunological correlates of highly active antiretroviral therapy (HAART)-induced suppression of human immunodeficiency virus type 1 (HIV-1) replication have been investigated. 20 HIV-1-infected patients with mean CD4 1 T cell count of 298/m l, plasma viral load of 4´7 log 10 copies/ml and naive for protease inhibitors (PI) were studied during12 months of HAART. An increased number of both CD4 1 and CD8 1 naive T cells and a normalization of the frequency of CCR5-and CXCR4-expressing CD4 1 T cells were readily observed after starting therapy. Single cell analysis of cytokine production after 12 months of HAART showed an increased number of interleukin (IL)-2-, but not IL-4-and (IFN)-g-, producing T cells and a decreased percentage of CD8 1 IFN-g 1 cells. A correlation between the frequency of IFN-g-producing T cells and that of memory, CCR5 1 and CD95 1 T cells was demonstrated in both CD4 1 and CD8 1 subsets. The diversity of T cell receptor (TCR) variable beta (BV) chain repertoire significantly increased after 12 months of HAART within the CD4 1 but not the CD8 1 T cell subset. However, the level of perturbation of the third complementaritydetermining region (CDR3), was not significantly modified by effective therapy. The number of anti-HIV Gag and Pol cytotoxic T lymphocytes precursors (CTLp) decreased during HAART and highly correlated with the CD8 IFN-g response. Ameliorated clinical conditions were observed in all patients in absence of any opportunistic infections during all the study period. These observations indicate that a better restoration of immunity may be obtained in patients starting HAART at less advanced stages of the disease.

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“…In the case of HIV infection in which models have also predicted loss of infected cells and estimated their rate of loss, ␦, direct validation has been possible by measuring the rate of decline of the number of infected cells in vitro 26 and in vivo through sequential tonsilar biopsies. 27 In the case of HCV infection, such direct observation has not been possible. However, Neumann et al 1 showed that second-phase slope was correlated with baseline ALT and histological activity index, suggesting but not proving a relationship with cell death.…”

mentioning

confidence: 99%

New kinetic models for the hepatitis C virus

et al. 2005

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K inetic models of hepatitis C virus (HCV) RNA decay induced by interferon (IFN) therapy have been developed by us and others. [1][2][3][4][5][6] The models, inspired by previous work on HIV and hepatitis B virus kinetics, 7-9 stimulated the collection of frequent viral loads and alanine aminotransferase (ALT) measurements after the initiation of therapy that revealed previously unknown kinetic patterns of HCV RNA change. The models have successfully summarized much of these new kinetic data and have given insights into features of HCV biology in vivo, such as the rate of virion clearance and the daily rate of virion production. More importantly from a clinical perspective, the models have allowed quantification of the antiviral effects of therapy and thus have made comparison of the antiviral effectiveness of different drug regimens possible using data collected over short intervals.

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Kinetics of Response in Lymphoid Tissues to Antiretroviral Therapy of HIV-1 Infection

Cited by 542 publications

References 16 publications

Persistence of Infectious HIV on Follicular Dendritic Cells

Persistence of Infectious HIV on Follicular Dendritic Cells

T cell responses to highly active antiretroviral therapy defined by chemokine receptors expression, cytokine production, T cell receptor repertoire and anti-HIV T-lymphocyte activity

New kinetic models for the hepatitis C virus

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