Influence of Host Gene Transcription Level and Orientation on HIV-1 Latency in a Primary-Cell Model

Shan, Liang; Yang, Hung‐Chih; Rabi, S. Alireza; Bravo, Héctor Corrada; Shroff, Neeta S.; Irizarry, Rafael A.; Zhang, Hao; Margolick, Joseph B.; Siliciano, Janet D.; Siliciano, Robert F.

doi:10.1128/jvi.02536-10

Cited by 102 publications

(109 citation statements)

References 63 publications

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“…We examined the impact of exogenous cellular activation on viral budding and found that activated cells produced considerably more virus than unactivated cells across all patient groups. Sequential Analysis Gene Expression (SAGE) analysis recently performed by our group (71) shows that activated CD4 + T cells universally have higher expression of cellular factors like Rab9 (68), Tip47 (72), and TSG101 (69), which are involved in virus assembly and budding. Using qPCR, we confirmed this finding, observing that Rab9 and TSG101 are up-regulated in CD4 + T cells activated with PHA or CD3 and CD28 antibodies compared with unstimulated CD4 + T cells from uninfected donors.…”

Section: Discussionmentioning

confidence: 99%

CD4⁺T cells from elite suppressors are more susceptible to HIV-1 but produce fewer virions than cells from chronic progressors

O’Connell¹,

Rabi²,

Siliciano

et al. 2011

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

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Elite suppressors/controllers (ES) are HIV-1-infected individuals who maintain stable CD4 + T-cell counts and viral loads of <50 copies/mL without antiretroviral therapy. Research has predominantly focused on immune factors contributing to the control of viral replication in these patients. A more fundamental question, however, is whether there are differences in the nature of CD4 + Tcell infection in ES compared with viremic patients. Here, we compare chronic progressor (CP), ES, and uninfected donors in terms of three aspects of CD4 + T-cell infection: cellular susceptibility to infection, death of infected cells, and production of virus from infected cells. Using multiple methods of infection and both single-cycle and replication-competent virus, we show that unmanipulated CD4 + T-cell populations from ES are actually more susceptible to HIV-1 infection than those populations from CP. Depletion of highly susceptible cells in CP may contribute to this difference. Using 7AAD and AnnexinV staining, we show that infected cells die more rapidly than uninfected cells, but the increased death of infected cells from CP and ES is proportional. Finally, using an assay for measuring virus production, we show that virus production by cells from CP is high compared with virus production by cells from ES or uninfected donors. This higher virus production is linked to cellular activation levels. These data identify fundamental differences in chronic infection of ES and CP that likely contribute to differential HIV-1 disease progression.burst size | cell death

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Section: Discussionmentioning

confidence: 99%

CD4⁺T cells from elite suppressors are more susceptible to HIV-1 but produce fewer virions than cells from chronic progressors

O’Connell¹,

Rabi²,

Siliciano

et al. 2011

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

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“…Virion production may also vary as a result of differences in proviral transcription. Integrations in inducible genes could contribute to higher levels of virion production, but could also lead to lower virion production from transcriptional interference (15,20,21). Epigenetic modifications that promote or inhibit HIV-1 transcription (22) may differ between individual infected cells.…”

Section: Iv-1 Virion Production From Resting Cd4mentioning

confidence: 99%

HIV-1 Virion Production from Single Inducible Proviruses following T-Cell Activation Ex Vivo

Bui

Mellors

Cillo

2016

J Virol

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Quantifying induced virion production from single proviruses is important for assessing the effects of HIV-1 latency reversal agents. Limiting dilution ex vivo cultures of resting CD4 ؉ T cells from 14 HIV-positive volunteers revealed that virion production after T-cell activation from individual proviruses varies by 10,000-fold to 100,000-fold. High-producing proviruses were associated with increases in cell-associated HIV-1 DNA levels, suggesting that reactivated proviruses proliferate. Single-cell analyses are needed to investigate differences in proviral expansion and virus production following latency reversal.

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“…Therefore, PIs can in principle also inhibit integration by preventing the formation of functional IN. Due to the heterogeneous nature of HIV-1 integration sites within the human genome (39,40), available assays for integration, such as Alu-PCR-based assays (41)(42)(43), lack the precision required for analyzing the dose-response curves of PIs at the integration step. Instead, we utilized VSV-G pseudotyped viruses, which are inhibited only at postentry steps ( Figure 2), to quantify the combined inhibition by PIs of all postentry steps, including integration ( Figure 3).…”

Section: (Equation 4)mentioning

confidence: 99%

Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance

Rabi

Laird²,

Durand³

et al. 2013

J. Clin. Invest.

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126

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HIV-1 protease inhibitors (PIs) are among the most effective antiretroviral drugs. They are characterized by highly cooperative dose-response curves that are not explained by current pharmacodynamic theory. An unresolved problem affecting the clinical use of PIs is that patients who fail PI-containing regimens often have virus that lacks protease mutations, in apparent violation of fundamental evolutionary theory. Here, we show that these unresolved issues can be explained through analysis of the effects of PIs on distinct steps in the viral life cycle. We found that PIs do not affect virion release from infected cells but block entry, reverse transcription, and post-reverse transcription steps. The overall dose-response curves could be reconstructed by combining the curves for each step using the Bliss independence principle, showing that independent inhibition of multiple distinct steps in the life cycle generates the highly cooperative dose-response curves that make these drugs uniquely effective. Approximately half of the inhibitory potential of PIs is manifest at the entry step, likely reflecting interactions between the uncleaved Gag and the cytoplasmic tail (CT) of the Env protein. Sequence changes in the CT alone, which are ignored in current clinical tests for PI resistance, conferred PI resistance, providing an explanation for PI failure without resistance.

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Influence of Host Gene Transcription Level and Orientation on HIV-1 Latency in a Primary-Cell Model

Cited by 102 publications

References 63 publications

CD4⁺T cells from elite suppressors are more susceptible to HIV-1 but produce fewer virions than cells from chronic progressors

CD4⁺T cells from elite suppressors are more susceptible to HIV-1 but produce fewer virions than cells from chronic progressors

HIV-1 Virion Production from Single Inducible Proviruses following T-Cell Activation Ex Vivo

Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance

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Influence of Host Gene Transcription Level and Orientation on HIV-1 Latency in a Primary-Cell Model

Cited by 102 publications

References 63 publications

CD4+T cells from elite suppressors are more susceptible to HIV-1 but produce fewer virions than cells from chronic progressors

CD4+T cells from elite suppressors are more susceptible to HIV-1 but produce fewer virions than cells from chronic progressors

HIV-1 Virion Production from Single Inducible Proviruses following T-Cell Activation Ex Vivo

Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance

Contact Info

Product

Resources

About

CD4⁺T cells from elite suppressors are more susceptible to HIV-1 but produce fewer virions than cells from chronic progressors

CD4⁺T cells from elite suppressors are more susceptible to HIV-1 but produce fewer virions than cells from chronic progressors