Faculty Opinions recommendation of Understanding the slow depletion of memory CD4+ T cells in HIV infection.

Human immunodeficiency virus (HIV) can infect resting CD4 T cells residing in lymphoid tissues but not those circulating in peripheral blood. The molecular mechanisms producing this difference remain unknown. We explored the potential role of the tissue microenvironment and its influence on the action of the antiviral factor APOBEC3G (A3G) in regulating permissivity to HIV infection. We found that endogenous IL-2 and -15 play a key role in rendering resident naive CD4 T cells susceptible to HIV infection. Infection of memory CD4 T cells also requires endogenous soluble factors, but not IL-2 or -15. A3G is found in a high molecular mass complex in HIV infection–permissive, tissue-resident naive CD4 T cells but resides in a low molecular mass form in nonpermissive, blood-derived naive CD4 T cells. Upon treatment with endogenous soluble factors, these cells become permissive for HIV infection, as low molecular mass A3G is induced to assemble into high molecular mass complexes. These findings suggest that in lymphoid tissues, endogenous soluble factors, likely including IL-2 and -15 and others, stimulate the formation of high molecular mass A3G complexes in tissue-resident naive CD4 T cells, thereby relieving the potent postentry restriction block for HIV infection conferred by low molecular mass A3G.

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Plasmacytoid dendritic cells have divergent effects on HIV infection of initial target cells and induce a pro-retention phenotype

PLoS Pathogens ◽

10.1371/journal.ppat.1009522 ◽

2021 ◽

Vol 17 (4) ◽

pp. e1009522

Author(s):

Orion Tong ◽

Gabriel Duette ◽

Thomas Ray O’Neil ◽

Caroline M. Royle ◽

Hafsa Rana ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Hiv Infection ◽

Reverse Transcriptase ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Target Cells ◽

Ccr5 Expression ◽

Memory Cd4 T Cells

Although HIV infection inhibits interferon responses in its target cells in vitro, interferon signatures can be detected in vivo soon after sexual transmission, mainly attributed to plasmacytoid dendritic cells (pDCs). In this study, we examined the physiological contributions of pDCs to early HIV acquisition using coculture models of pDCs with myeloid DCs, macrophages and the resting central, transitional and effector memory CD4 T cell subsets. pDCs impacted infection in a cell-specific manner. In myeloid cells, HIV infection was decreased via antiviral effects, cell maturation and downregulation of CCR5 expression. In contrast, in resting memory CD4 T cells, pDCs induced a subset-specific increase in intracellular HIV p24 protein expression without any activation or increase in CCR5 expression, as measured by flow cytometry. This increase was due to reactivation rather than enhanced viral spread, as blocking HIV entry via CCR5 did not alter the increased intracellular p24 expression. Furthermore, the load and proportion of cells expressing HIV DNA were restricted in the presence of pDCs while reverse transcriptase and p24 ELISA assays showed no increase in particle associated reverse transcriptase or extracellular p24 production. In addition, PDCs also markedly induced the expression of CD69 on infected CD4 T cells and other markers of CD4 T cell tissue retention. These phenotypic changes showed marked parallels with resident memory CD4 T cells isolated from anogenital tissue using enzymatic digestion. Production of IFNα by pDCs was the main driving factor for all these results. Thus, pDCs may reduce HIV spread during initial mucosal acquisition by inhibiting replication in myeloid cells while reactivating latent virus in resting memory CD4 T cells and retaining them for immune clearance.

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Faculty Opinions recommendation of Transcription factor FOXO3a controls the persistence of memory CD4(+) T cells during HIV infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1104534.560577 ◽

2008 ◽

Author(s):

Scott Sieg ◽

Nicholas Funderburg

Keyword(s):

T Cells ◽

Transcription Factor ◽

Hiv Infection ◽

Cd4 T Cells ◽

Memory Cd4 T Cells

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THE STUDY OF HIV INFECTION IN CHINESE ANTIRETROVIRAL THERAPY PATIENTS

Journal of Biological System ◽

10.1142/s0218339014500041 ◽

2014 ◽

Vol 22 (01) ◽

pp. 73-88

Author(s):

JIE LOU ◽

HONGMEI ZHANG ◽

QUANBI ZHAO ◽

LINGJIE LIAO ◽

LITAO HAN

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Hiv Infection ◽

Cd4 T Cells ◽

Mathematics Model ◽

Highly Active ◽

Immunodeficiency Virus ◽

Memory Cd4 T Cells ◽

Insight Into

Analysis of changes in viral load after initiation of treatment with potent antiretroviral agents has provided substantial insights into the dynamics of human immunodeficiency virus type 1. We built a simple mathematics model to study the effect of latent-infected resting memory CD4+ T cells during the HIV infection and highly active anti-retroviral therapy (HAART). Through analysis of eight patients who received HAART in China, we have an insight into the mechanisms of resting memory CD4+ T cells in HIV infection. Simulations show that new infections still exist in the eight patients even under the HAART. Also, because of the long half-life of resting infected memory CD4+ T cells, removal of HIV from patient could take considerably longer time or be unattainable.

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Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation

Blood ◽

10.1182/blood-2010-09-309591 ◽

2011 ◽

Vol 117 (10) ◽

pp. 2791-2799 ◽

Cited By ~ 472

Author(s):

Kristina Allers ◽

Gero Hütter ◽

Jörg Hofmann ◽

Christoph Loddenkemper ◽

Kathrin Rieger ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Hiv Infection ◽

Cell Transplantation ◽

Cd4 T Cells ◽

Immune Reconstitution ◽

Productive Infection ◽

Viral Reservoir ◽

Memory Cd4 T Cells

Abstract HIV entry into CD4+ cells requires interaction with a cellular receptor, generally either CCR5 or CXCR4. We have previously reported the case of an HIV-infected patient in whom viral replication remained absent despite discontinuation of antiretroviral therapy after transplantation with CCR5Δ32/Δ32 stem cells. However, it was expected that the long-lived viral reservoir would lead to HIV rebound and disease progression during the process of immune reconstitution. In the present study, we demonstrate successful reconstitution of CD4+ T cells at the systemic level as well as in the gut mucosal immune system after CCR5Δ32/Δ32 stem cell transplantation, while the patient remains without any sign of HIV infection. This was observed although recovered CD4+ T cells contain a high proportion of activated memory CD4+ T cells, ie, the preferential targets of HIV, and are susceptible to productive infection with CXCR4-tropic HIV. Furthermore, during the process of immune reconstitution, we found evidence for the replacement of long-lived host tissue cells with donor-derived cells, indicating that the size of the viral reservoir has been reduced over time. In conclusion, our results strongly suggest that cure of HIV has been achieved in this patient.

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Understanding the Slow Depletion of Memory CD4+ T Cells in HIV Infection

PLoS Medicine ◽

10.1371/journal.pmed.0040177 ◽

2007 ◽

Vol 4 (5) ◽

pp. e177 ◽

Cited By ~ 37

Author(s):

Andrew Yates ◽

Jaroslav Stark ◽

Nigel Klein ◽

Rustom Antia ◽

Robin Callard

Keyword(s):

T Cells ◽

Hiv Infection ◽

Cd4 T Cells ◽

Memory Cd4 T Cells

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CD25+FoxP3+Memory CD4 T Cells Are Frequent Targets of HIV InfectionIn Vivo

Journal of Virology ◽

10.1128/jvi.00612-16 ◽

2016 ◽

Vol 90 (20) ◽

pp. 8954-8967 ◽

Cited By ~ 8

Author(s):

Mkunde Chachage ◽

Georgios Pollakis ◽

Edmund Osei Kuffour ◽

Kerstin Haase ◽

Asli Bauer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hiv Infection ◽

Cd4 T Cells ◽

T Cell Subsets ◽

Hiv Dna ◽

Active Viral Replication ◽

Memory Cd4 T Cells

ABSTRACTInterleukin 2 (IL-2) signaling through the IL-2 receptor alpha chain (CD25) facilitates HIV replicationin vitroand facilitates homeostatic proliferation of CD25+FoxP3+CD4+T cells. CD25+FoxP3+CD4+T cells may therefore constitute a suitable subset for HIV infection and plasma virion production. CD25+FoxP3+CD4+T cell frequencies, absolute numbers, and the expression of CCR5 and cell cycle marker Ki67 were studied in peripheral blood from HIV+and HIV−study volunteers. Different memory CD4+T cell subsets were then sorted for quantification of cell-associated HIV DNA and phylogenetic analyses of the highly variable EnvV1V3 region in comparison to plasma-derived virus sequences. In HIV+subjects, 51% (median) of CD25+FoxP3+CD4+T cells expressed the HIV coreceptor CCR5. Very high frequencies of Ki67+cells were detected in CD25+FoxP3+memory CD4+T cells (median, 27.6%) in comparison to CD25−FoxP3−memory CD4+T cells (median, 4.1%;P< 0.0001). HIV DNA content was 15-fold higher in CD25+FoxP3+memory CD4+T cells than in CD25−FoxP3−T cells (P= 0.003). EnvV1V3 sequences derived from CD25+FoxP3+memory CD4+T cells did not preferentially cluster with plasma-derived sequences. Quasi-identical cell-plasma sequence pairs were rare, and their proportion decreased with the estimated HIV infection duration. These data suggest that specific cellular characteristics of CD25+FoxP3+memory CD4+T cells might facilitate efficient HIV infectionin vivoand passage of HIV DNA to cell progeny in the absence of active viral replication. The contribution of this cell population to plasma virion production remains unclear.IMPORTANCEDespite recent advances in the understanding of AIDS virus pathogenesis, which cell subsets support HIV infection and replicationin vivois incompletely understood.In vitro, the IL-2 signaling pathway and IL-2-dependent cell cycle induction are essential for HIV infection of stimulated T cells. CD25+FoxP3+memory CD4 T cells, often referred to as regulatory CD4 T cells, depend on IL-2 signaling for homeostatic proliferationin vivo. Our results show that CD25+FoxP3+memory CD4+T cells often express the HIV coreceptor CCR5, are significantly more proliferative, and contain more HIV DNA than CD25−FoxP3−memory CD4 T cell subsets. The specific cellular characteristics of CD25+FoxP3+memory CD4+T cells probably facilitate efficient HIV infectionin vivoand passage of HIV DNA to cell progeny in the absence of active viral replication. However, the contribution of this cell subset to plasma viremia remains unclear.

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