A stable latent reservoir for HIV-1 in resting CD4+ T lymphocytes in infected children

Persaud, Deborah; Pierson, Theodore C.; Ruff, Christian T.; Finzi, Diana; Chadwick, Karen; Margolick, Joseph B.; Ruff, Andrea; Hutton, Nancy; Ray, Stuart C.; Siliciano, Robert F.

doi:10.1172/jci9006

Cited by 161 publications

(138 citation statements)

References 38 publications

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“…Models incorporating higher-order decay kinetics (30,31,53) suggest that therapy must last some 60 years to eradicate the virus (23,49). The predictions of these models may reflect the slow loss of virus from "reservoirs."…”

mentioning

confidence: 99%

Host Cell Gene Expression during Human Immunodeficiency Virus Type 1 Latency and Reactivation and Effects of Targeting Genes That Are Differentially Expressed in Viral Latency

Krishnan

Zeichner

2004

J Virol

103

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The existence of reservoirs of cells latently infected with human immunodeficiency virus (HIV) is a major obstacle to the elimination of HIV infection. We studied the changes in cellular gene expression that accompany the reactivation and completion of the lytic viral cycle in cell lines chronically infected with HIV-1. We found that several genes exhibited altered expression in the chronically infected cells compared to the uninfected parental cells prior to induction into lytic replication. A number of gene classes showed increased expression in the chronically infected cells, notably including genes encoding proteasomes, histone deacetylases, and many transcription factors. Following induction of the lytic replication cycle, we observed ordered, time-dependent changes in the cellular gene expression pattern. Approximately 1,740 genes, many of which fall into 385 known pathways, were differentially expressed (P < 0.001), indicating that completion of the HIV replication cycle is associated with distinct, temporally ordered changes in host cell gene expression. Maximum changes were observed in the early and intermediate phases of the lytic replication cycle. Since the changes in gene expression in chronically infected cells suggested that cells latently infected with HIV have a different gene expression profile than corresponding uninfected cells, we studied the expression profiles of three different chronically infected cell lines to determine whether they showed similar changes in common cellular genes and pathways. Thirty-two genes showed significant differential expression in all cell lines studied compared to their uninfected parental cell lines. Notable among them were cdc42 and lyn, which were downregulated and are required for HIV Nef binding and viral replication. Other genes previously unrelated to HIV latency or pathogenesis were also differentially expressed. To determine the effects of targeting products of the genes that were differentially expressed in latently infected cells, we treated the latently infected cells with a proteasome inhibitor, clastolactacystin-beta-lactone (CLBL), and an Egr1 activator, resveratrol. We found that treatment with CLBL and resveratrol stimulated lytic viral replication, suggesting that treatment of cells with agents that target cellular genes differentially expressed in latently infected cells can stimulate lytic replication. These findings may offer new insights into the interaction of the latently infected host cell and HIV and suggest therapeutic approaches for inhibiting HIV infection and for manipulating cells latently infected with HIV so as to trigger lytic replication.

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mentioning

confidence: 99%

Host Cell Gene Expression during Human Immunodeficiency Virus Type 1 Latency and Reactivation and Effects of Targeting Genes That Are Differentially Expressed in Viral Latency

Krishnan

Zeichner

2004

J Virol

103

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“…This finding is consistent with previous studies on MTCT of HIV-1 showing that either single or multiple variants can be transmitted vertically, [42][43][44] but multiple-strain infection during vertical transmission seems to be less frequent than infection initiated by a single or a few closely related maternal variants. [41][42][43][44][45][46][47] Phylogenetic analyses also showed relatively longer genetic distances between the viral populations of mothers and their children in all pairs, except for HP13, which could be due to the transmission of a minor variant from the mother to her child. 48 In the current study, evolution of HIV-1 strains (HP25), viral population shifts (HN46 and HN51), and switch of coreceptor usage from R5 to X4 (HN46) were also observed in the children.…”

Section: Discussionmentioning

confidence: 99%

Genetic Analyses of HIV-1 Strains Transmitted from Mother to Child in Northern Vietnam

Phan

Pham

et al. 2015

AIDS Research and Human Retroviruses

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We previously reported mother-to-child transmission of HIV-1 in nine (6.7%) of 135 children on nevirapine prophylaxis in Vietnam. In the current study, we investigated the appearance and profile of antiretroviral drug (ARV) resistance mutations, the predicted coreceptor usage, and the genetic diversity of HIV-1 strains isolated from the eight pairs of HIV-1-infected mothers and their children, who were followed up to 12 months after birth. Portions of the pol and env C2V3 regions of the HIV-1 strains were analyzed genetically. HIV-1 CRF01_AE RNA was detected in four (50%) children at delivery. Y181C, a nevirapine resistance mutation, appeared in two (25%) children 1 and 3 months after birth, respectively. No ARV resistance mutation was detected in the mothers, though three mothers were on ARV prophylaxis. Five mothers and their children harbored CCR5-tropic (R5) viruses. Two mothers harbored both R5 and CXCR4-tropic (X4) viruses, but their children harbored only R5 viruses even though the X4 viruses were dominant in the mothers. In the remaining one mother, HIV-1 RNA was not amplified and her child harbored both R5 and X4 viruses at birth, but only X4 virus 12 months after delivery. The infants' viruses were more homogeneous than their mothers' viruses (mean distance: 0.5% vs.

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“…gag-pol sequences with drug resistance mutations were obtained from the latent reservoir or plasma of compliant pediatric and adult patients who were failing HAART with consistently detectable viremia, as previously described (24,41,49). Isolates from the latent reservoir were obtained from replication-competent viruses grown out of the reservoir at a limiting dilution in cultures in which resting cells from patients were stimulated in vitro with mitogens and then cocultured in the presence of CD4 ϩ lymphoblasts from healthy donors (18).…”

Section: Methodsmentioning

confidence: 99%

“…ϩ T cells can serve as a permanent archive for all major forms of the virus present during the entire course of infection, including the original drug-sensitive forms as well as drug-resistant viruses that arise due to inadequate suppression of viral replication by antiretroviral drugs (41,49).…”

Section: Human Immunodeficiency Virus Type 1 (Hiv-1)-infected Individmentioning

confidence: 99%

“…Phylogenetic evidence suggests that the reemerging wild-type viruses are archival (29). At the present time, the only site in which wild-type viruses have been shown to persist despite prolonged replication of and selection for drug-resistant viruses is the latent reservoir in resting memory CD4 ϩ T cells (35,41,49). The considerations presented above suggest that patients failing HAART may derive benefit from continued treatment for two reasons, namely the residual susceptibility of the resistant viruses to the drug regimen and the diminished replication capacities of the resistant viruses.…”

Section: Human Immunodeficiency Virus Type 1 (Hiv-1)-infected Individmentioning

confidence: 99%

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Novel Single-Cell-Level Phenotypic Assay for Residual Drug Susceptibility and Reduced Replication Capacity of Drug-Resistant Human Immunodeficiency Virus Type 1

Zhang¹,

Zhou²,

Alcock³

et al. 2004

J Virol

Self Cite

167

172

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Human immunodeficiency virus type 1 (HIV-1)-infected individuals who develop drug-resistant virus during antiretroviral therapy may derive benefit from continued treatment for two reasons. First, drug-resistant viruses can retain partial susceptibility to the drug combination. Second, therapy selects for drug-resistant viruses that may have reduced replication capacities relative to archived, drug-sensitive viruses. We developed a novel single-cell-level phenotypic assay that allows these two effects to be distinguished and compared quantitatively. Patient-derived gag-pol sequences were cloned into an HIV-1 reporter virus that expresses an endoplasmic reticulum-retained Env-green fluorescent protein fusion. Flow cytometric analysis of single-round infections allowed a quantitative analysis of viral replication over a 4-log dynamic range. The assay faithfully reproduced known in vivo drug interactions occurring at the level of target cells. Simultaneous analysis of single-round infections by wild-type and resistant viruses in the presence and absence of the relevant drug combination divided the benefit of continued nonsuppressive treatment into two additive components, residual virus susceptibility to the drug combination and selection for drug-resistant variants with diminished replication capacities. In some patients with drug resistance, the dominant circulating viruses retained significant susceptibility to the combination. However, in other cases, the dominant drug-resistant viruses showed no residual susceptibility to the combination but had a reduced replication capacity relative to the wild-type virus. In this case, simplification of the regimen might still allow adequate suppression of the wild-type virus. In a third pattern, the resistant viruses had no residual susceptibility to the relevant drug regimen but nevertheless had a replication capacity equivalent to that of wild-type virus. In such cases, there is no benefit to continued treatment. Thus, the ability to simultaneously analyze residual susceptibility and reduced replication capacity of drug-resistant viruses may provide a basis for rational therapeutic decisions in the setting of treatment failure.

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A stable latent reservoir for HIV-1 in resting CD4+ T lymphocytes in infected children

Cited by 161 publications

References 38 publications

Host Cell Gene Expression during Human Immunodeficiency Virus Type 1 Latency and Reactivation and Effects of Targeting Genes That Are Differentially Expressed in Viral Latency

Host Cell Gene Expression during Human Immunodeficiency Virus Type 1 Latency and Reactivation and Effects of Targeting Genes That Are Differentially Expressed in Viral Latency

Genetic Analyses of HIV-1 Strains Transmitted from Mother to Child in Northern Vietnam

Novel Single-Cell-Level Phenotypic Assay for Residual Drug Susceptibility and Reduced Replication Capacity of Drug-Resistant Human Immunodeficiency Virus Type 1

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