HLA-DR+CD38+CD4+T Lymphocytes Have Elevated CCR5 Expression and Produce the Majority of R5-Tropic HIV-1 RNAInVivo

Meditz, Amie L.; Haas, Michelle; Folkvord, Joy M.; Melander, Kelsey; Young, Russ; McCarter, Martin D.; MaWhinney, Samantha; Campbell, Thomas; Lie, Yolanda; Coakley, Eoin; Levy, David; Connick, Elizabeth

doi:10.1128/jvi.02529-10

Cited by 79 publications

(90 citation statements)

References 48 publications

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“…Somewhat contrary to expectations, but consistent with previous observations from our group and others (13,22), we found total HIV DNA to be present in equivalent proportions across all resting/activated subsets before the commencement of ART (Fig. 2).…”

Section: Discussioncontrasting

confidence: 55%

HIV DNA Subspecies Persist in both Activated and Resting Memory CD4 ⁺ T Cells during Antiretroviral Therapy

Murray

Zaunders²,

McBride

et al. 2014

J Virol

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The latent HIV reservoir is a major impediment to curing HIV infection. The contribution of CD4؉ T cell activation status to the establishment and maintenance of the latent reservoir was investigated by enumerating viral DNA components in a cohort of 12 individuals commencing antiretroviral therapy (ART) containing raltegravir, an integrase inhibitor. Prior to ART, the levels of total HIV DNA were similar across HLA-DR IMPORTANCE It is generally believed that HIV is not cleared by extensive antiretroviral therapy (ART) due to the difficulty in eradicating the latent reservoir in resting CD4؉ T cells. New therapies that attempt to activate this reservoir so that immune or viral cytopathic mechanisms can remove those infected cells are currently being investigated. However, results obtained in this research indicate that activation, at least on some level, already occurs within this reservoir. Furthermore, we are the first to describe the dynamics of different HIV DNA species in resting and activated memory CD4؉ T cell subsets that point to the role different levels of activation play in maintaining the HIV reservoir.

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Section: Discussioncontrasting

confidence: 55%

HIV DNA Subspecies Persist in both Activated and Resting Memory CD4 ⁺ T Cells during Antiretroviral Therapy

Murray

Zaunders²,

McBride

et al. 2014

J Virol

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“…25 Similarly, study of infection of resting cells has generally used the lack of expression of HLA-DR, CD25, and CD69 as markers of activation. 51 Infection of activated CD38 + CD4 + T cells in PBMCs in vitro and lymphoid tissue in vivo has been investigated 52 ; however, circulating CD38…”

Section: Discussionmentioning

confidence: 99%

“…51,52,58 In those latter studies, activated CD4 + T cells were compared to nonactivated CD4 + T cells, which presumably contained substantial proportions of naive CD4 + T cells, which contain approximately 10-fold less HIV-1 DNA than memory CD4 + T cells. 45,59 One study defined HLA-DR -CD25 -CD69 -as resting cells, 51 but we have found that this subset contains CD38…”

Section: Hiv-1 Dna In Non-gut-homing Cd4mentioning

confidence: 99%

The Majority of HIV Type 1 DNA in Circulating CD4⁺T Lymphocytes Is Present in Non-Gut-Homing Resting Memory CD4⁺T Cells

McBride

Xu²,

Bailey³

et al. 2013

AIDS Research and Human Retroviruses

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Memory CD4+ T lymphocytes in peripheral blood that express integrins a4ß7 preferentially recirculate through gut-associated lymphoid tissue (GALT), a proposed site of significant HIV-1 replication. Tregs and activated CD4 + T cells in GALT could also be particularly susceptible to infection. We therefore hypothesized that infection of these subsets of memory CD4+ T cells may contribute disproportionately to the HIV-1 reservoir. A cross-sectional study of CD4 + T cell subsets of memory CD45RO + cells in peripheral blood mononuclear cells (PBMCs) was conducted using leukapheresis from eight subjects with untreated chronic HIV-1 infection. Realtime polymerase chain reaction (PCR) was used to quantify total and integrated HIV-1 DNA levels from memory CD4 + T cells sorted into integrin b7 + vs. b7 -, CD25 + CD127 low Treg vs. CD127 high , and activated CD38 + vs. CD38 -. More than 80% of total HIV-1 DNA was found to reside in the integrin b7-negative nongut-homing subset of CD45RO + memory CD4 + T cells. Less than 10% was found in highly purified Tregs or CD38+ activated memory cells. Similarly, integrated HIV-1 DNA copies were found to be more abundant in resting non-gut-homing memory CD4 + T cells (76%) than in their activated counterparts (23%). Our investigations showed that the majority of both total and integrated HIV-1 DNA was found within non-gut-homing resting CD4 + T cells.

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“…The number of activated CD4 + T cells, as assessed in cervical mononuclear cell preparations, is increased during mucosal inflammation and may promote HIV replication (39), and the genital HIV RNA level itself is an independent predictor of sexual transmission (40). A recent report on cytobrush-derived cervical cells from HIV + women suggested that genital CD4 T cell activation was associated with CD4 T cell depletion (41).…”

Section: Discussionmentioning

confidence: 99%

Stable CD4 Expression and Local Immune Activation in the Ectocervical Mucosa of HIV-Infected Women

Hirbod

Kimani

Tjernlund

et al. 2013

The Journal of Immunology

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Studies using genital tissue samples from HIV-infected women might provide important information about HIV susceptibility and transmission. In this study, ectocervical biopsies were obtained from 20 HIV-seropositive (HIV+) Kenyan female sex workers (FSW) and 20 HIV-seronegative lower risk (HIV− LR) women. To control for the impact of sex work, 20 HIV− FSW were also recruited. Immune molecules were assessed in situ by immunohistochemistry and for mRNA expression by quantitative PCR. The HIV+ women were reportedly infected for a median of 3 y (1–21 y), with a median viral load of 11,735 copies/ml (20–648,000 copies/ml). These women had significantly lower CD4 blood cell counts than the HIV− LR women but comparable levels of CD4 expression in ectocervix. Whereas cellular markers were similar between the HIV+ group and the HIV− LR women, the HIV-binding molecules CCR5, dendritic cell–specific intercellular adhesion molecule-3–grabbing nonintegrin, and mannose receptor as well as the inflammatory markers CD69, IFN-γ, IL-6, and IL-22 were significantly upregulated in the HIV+ group. As compared with the HIV− FSW women, the HIV+ women had significantly upregulated levels of CD4, CD3, CCR5, Langerin, dendritic cell–specific intercellular adhesion molecule-3–grabbing nonintegrin, and mannose receptor as well as inflammatory cytokines. The CD4 cell depletion previously seen in the gut mucosa of HIV-infected individuals was thus not observed in the ectocervical mucosa. Stable CD4 cell expression and local immune activation in the lower female genital tract may promote viral replication and genital shedding and increase the risk of sexual HIV transmission.

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HLA-DR⁺CD38⁺CD4⁺T Lymphocytes Have Elevated CCR5 Expression and Produce the Majority of R5-Tropic HIV-1 RNAInVivo

Abstract: Percentages of activated T cells correlate with HIV-؊ DR/38 subsets (P < 0.001 for both). Median HIV-1

Cited by 79 publications

References 48 publications

HIV DNA Subspecies Persist in both Activated and Resting Memory CD4 ⁺ T Cells during Antiretroviral Therapy

HIV DNA Subspecies Persist in both Activated and Resting Memory CD4 ⁺ T Cells during Antiretroviral Therapy

The Majority of HIV Type 1 DNA in Circulating CD4⁺T Lymphocytes Is Present in Non-Gut-Homing Resting Memory CD4⁺T Cells

Stable CD4 Expression and Local Immune Activation in the Ectocervical Mucosa of HIV-Infected Women

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HLA-DR+CD38+CD4+T Lymphocytes Have Elevated CCR5 Expression and Produce the Majority of R5-Tropic HIV-1 RNAInVivo

Abstract: Percentages of activated T cells correlate with HIV-؊ DR/38 subsets (P < 0.001 for both). Median HIV-1

Cited by 79 publications

References 48 publications

HIV DNA Subspecies Persist in both Activated and Resting Memory CD4 + T Cells during Antiretroviral Therapy

HIV DNA Subspecies Persist in both Activated and Resting Memory CD4 + T Cells during Antiretroviral Therapy

The Majority of HIV Type 1 DNA in Circulating CD4+T Lymphocytes Is Present in Non-Gut-Homing Resting Memory CD4+T Cells

Stable CD4 Expression and Local Immune Activation in the Ectocervical Mucosa of HIV-Infected Women

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Product

Resources

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HLA-DR⁺CD38⁺CD4⁺T Lymphocytes Have Elevated CCR5 Expression and Produce the Majority of R5-Tropic HIV-1 RNAInVivo

HIV DNA Subspecies Persist in both Activated and Resting Memory CD4 ⁺ T Cells during Antiretroviral Therapy

HIV DNA Subspecies Persist in both Activated and Resting Memory CD4 ⁺ T Cells during Antiretroviral Therapy

The Majority of HIV Type 1 DNA in Circulating CD4⁺T Lymphocytes Is Present in Non-Gut-Homing Resting Memory CD4⁺T Cells