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CD4 depletion in SIV-infected macaques results in macrophage and microglia infection with rapid turnover of infected cells.

Micci L, Alvarez X, Iriele RI, Ortiz AM, Ryan ES, McGary CS, Deleage C, McAtee BB, He T, Apetrei C, Easley K, Pahwa S, Collman RG, Derdeyn CA, Davenport MP, Estes JD, Silvestri G, Lackner AA, Paiardini M - PLoS Pathog. (2014)

Bottom Line: In rhesus macaques (RMs), experimental depletion of CD4+ T-cells prior to SIV infection results in higher viremia and emergence of CD4-independent SIV-envelopes.In this study we used the rhesus recombinant anti-CD4 antibody CD4R1 to deplete RM CD4+ T-cells prior to SIVmac251 infection and investigate the sources of the increased viral burden and the lifespan of productively infected cells.We believe these findings have important implications for HIV eradication studies.

View Article: PubMed Central - PubMed

Affiliation: Division of Microbiology & Immunology, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.

ABSTRACT
In rhesus macaques (RMs), experimental depletion of CD4+ T-cells prior to SIV infection results in higher viremia and emergence of CD4-independent SIV-envelopes. In this study we used the rhesus recombinant anti-CD4 antibody CD4R1 to deplete RM CD4+ T-cells prior to SIVmac251 infection and investigate the sources of the increased viral burden and the lifespan of productively infected cells. CD4-depleted animals showed (i) set-point viral load two-logs higher than controls; (ii) macrophages constituting 80% of all SIV vRNA+ cells in lymph node and mucosal tissues; (iii) substantial expansion of pro-inflammatory monocytes; (iv) aberrant activation and infection of microglial cells; and (v) lifespan of productively infected cells significantly longer in comparison to controls, but markedly shorter than previously estimated for macrophages. The net effect of CD4+ T-cell depletion is an inability to control SIV replication and a shift in the tropism of infected cells to macrophages, microglia, and, potentially, other CD4-low cells which all appear to have a shortened in vivo lifespan. We believe these findings have important implications for HIV eradication studies.

No MeSH data available.


Related in: MedlinePlus

Study design and extent of CD4+ T-cell depletion induced by CD4R1.(a) Time line of the study indicating the days in which CD4R1 was administered, SIVmac251 infection performed, and ART initiated, as well as the experimental points at which blood (PB), bone marrow (BM), lymph nodes (LN) and rectal biopsies were collected. (b,c) Longitudinal levels (mean±S.E) of the circulating CD4+ T-cells expressed as absolute number (b) or fraction (c) of CD3+ T-cells in severely depleted (orange square; n = 3), intermediately depleted (blue diamond; n = 5) or undepleted control (black circle; n = 4) RMs. In both severely- and intermediately-depleted RMs, the percentage and absolute count of CD4+ T-cells were significantly lower (P<0.01) than controls at all experimental points post-depletion. (d) Representative flow plots showing the fraction of CD4+ T-cells pre- and post-depletion (day −11) in one severely (top) and one intermediately (bottom) depleted RMs. (e) Levels of CD4+ T-cells expressed as fraction of CD3+ T-cells in PB, BM and LN immediately before SIV infection (day 0) in severely depleted (S; n = 3), intermediately depleted (I; n = 5) or control (C; n = 4) RMs. In both severely- and intermediately-depleted RMs, the percentages of CD4+ T-cells were significantly lower (P<0.01) than controls. (f) Longitudinal levels (mean±S.E) of the fraction of circulating CD4+ T-cells expressed Ki-67 in severely depleted (n = 3), intermediately depleted (n = 5) or control RMs (n = 4). The gray box in the graphs of panels b, c, f indicates the post-depletion, pre-infection window. *P<0.01.
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ppat-1004467-g001: Study design and extent of CD4+ T-cell depletion induced by CD4R1.(a) Time line of the study indicating the days in which CD4R1 was administered, SIVmac251 infection performed, and ART initiated, as well as the experimental points at which blood (PB), bone marrow (BM), lymph nodes (LN) and rectal biopsies were collected. (b,c) Longitudinal levels (mean±S.E) of the circulating CD4+ T-cells expressed as absolute number (b) or fraction (c) of CD3+ T-cells in severely depleted (orange square; n = 3), intermediately depleted (blue diamond; n = 5) or undepleted control (black circle; n = 4) RMs. In both severely- and intermediately-depleted RMs, the percentage and absolute count of CD4+ T-cells were significantly lower (P<0.01) than controls at all experimental points post-depletion. (d) Representative flow plots showing the fraction of CD4+ T-cells pre- and post-depletion (day −11) in one severely (top) and one intermediately (bottom) depleted RMs. (e) Levels of CD4+ T-cells expressed as fraction of CD3+ T-cells in PB, BM and LN immediately before SIV infection (day 0) in severely depleted (S; n = 3), intermediately depleted (I; n = 5) or control (C; n = 4) RMs. In both severely- and intermediately-depleted RMs, the percentages of CD4+ T-cells were significantly lower (P<0.01) than controls. (f) Longitudinal levels (mean±S.E) of the fraction of circulating CD4+ T-cells expressed Ki-67 in severely depleted (n = 3), intermediately depleted (n = 5) or control RMs (n = 4). The gray box in the graphs of panels b, c, f indicates the post-depletion, pre-infection window. *P<0.01.

Mentions: CD4+ T-cells were depleted in eight RMs using a single administration of CD4R1 antibody at 50 mg/kg, as recommended by the “NIH Nonhuman Primate Reagent Resource” protocol (Figure 1a). Of note, this regimen generated variable levels of CD4+ T-cell depletion in our pilot studies. Four untreated animals were included as controls. All 12 RMs were infected with SIVmac251 (i.v. 3,000 TCID50) six weeks post CD4R1 treatment, in order to avoid the possible confounding effect of direct antiviral activity of the CD4R1 antibody. At day-52 post-infection (p.i.) all animals were treated with a three-drugs antiretroviral regimen (PMPA, FTC, raltegravir). Blood, bone marrow aspirate (BM), lymph nodes (LN) and rectal biopsies (RB) were collected longitudinally and at necropsy (Figure 1a).


CD4 depletion in SIV-infected macaques results in macrophage and microglia infection with rapid turnover of infected cells.

Micci L, Alvarez X, Iriele RI, Ortiz AM, Ryan ES, McGary CS, Deleage C, McAtee BB, He T, Apetrei C, Easley K, Pahwa S, Collman RG, Derdeyn CA, Davenport MP, Estes JD, Silvestri G, Lackner AA, Paiardini M - PLoS Pathog. (2014)

Study design and extent of CD4+ T-cell depletion induced by CD4R1.(a) Time line of the study indicating the days in which CD4R1 was administered, SIVmac251 infection performed, and ART initiated, as well as the experimental points at which blood (PB), bone marrow (BM), lymph nodes (LN) and rectal biopsies were collected. (b,c) Longitudinal levels (mean±S.E) of the circulating CD4+ T-cells expressed as absolute number (b) or fraction (c) of CD3+ T-cells in severely depleted (orange square; n = 3), intermediately depleted (blue diamond; n = 5) or undepleted control (black circle; n = 4) RMs. In both severely- and intermediately-depleted RMs, the percentage and absolute count of CD4+ T-cells were significantly lower (P<0.01) than controls at all experimental points post-depletion. (d) Representative flow plots showing the fraction of CD4+ T-cells pre- and post-depletion (day −11) in one severely (top) and one intermediately (bottom) depleted RMs. (e) Levels of CD4+ T-cells expressed as fraction of CD3+ T-cells in PB, BM and LN immediately before SIV infection (day 0) in severely depleted (S; n = 3), intermediately depleted (I; n = 5) or control (C; n = 4) RMs. In both severely- and intermediately-depleted RMs, the percentages of CD4+ T-cells were significantly lower (P<0.01) than controls. (f) Longitudinal levels (mean±S.E) of the fraction of circulating CD4+ T-cells expressed Ki-67 in severely depleted (n = 3), intermediately depleted (n = 5) or control RMs (n = 4). The gray box in the graphs of panels b, c, f indicates the post-depletion, pre-infection window. *P<0.01.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4214815&req=5

ppat-1004467-g001: Study design and extent of CD4+ T-cell depletion induced by CD4R1.(a) Time line of the study indicating the days in which CD4R1 was administered, SIVmac251 infection performed, and ART initiated, as well as the experimental points at which blood (PB), bone marrow (BM), lymph nodes (LN) and rectal biopsies were collected. (b,c) Longitudinal levels (mean±S.E) of the circulating CD4+ T-cells expressed as absolute number (b) or fraction (c) of CD3+ T-cells in severely depleted (orange square; n = 3), intermediately depleted (blue diamond; n = 5) or undepleted control (black circle; n = 4) RMs. In both severely- and intermediately-depleted RMs, the percentage and absolute count of CD4+ T-cells were significantly lower (P<0.01) than controls at all experimental points post-depletion. (d) Representative flow plots showing the fraction of CD4+ T-cells pre- and post-depletion (day −11) in one severely (top) and one intermediately (bottom) depleted RMs. (e) Levels of CD4+ T-cells expressed as fraction of CD3+ T-cells in PB, BM and LN immediately before SIV infection (day 0) in severely depleted (S; n = 3), intermediately depleted (I; n = 5) or control (C; n = 4) RMs. In both severely- and intermediately-depleted RMs, the percentages of CD4+ T-cells were significantly lower (P<0.01) than controls. (f) Longitudinal levels (mean±S.E) of the fraction of circulating CD4+ T-cells expressed Ki-67 in severely depleted (n = 3), intermediately depleted (n = 5) or control RMs (n = 4). The gray box in the graphs of panels b, c, f indicates the post-depletion, pre-infection window. *P<0.01.
Mentions: CD4+ T-cells were depleted in eight RMs using a single administration of CD4R1 antibody at 50 mg/kg, as recommended by the “NIH Nonhuman Primate Reagent Resource” protocol (Figure 1a). Of note, this regimen generated variable levels of CD4+ T-cell depletion in our pilot studies. Four untreated animals were included as controls. All 12 RMs were infected with SIVmac251 (i.v. 3,000 TCID50) six weeks post CD4R1 treatment, in order to avoid the possible confounding effect of direct antiviral activity of the CD4R1 antibody. At day-52 post-infection (p.i.) all animals were treated with a three-drugs antiretroviral regimen (PMPA, FTC, raltegravir). Blood, bone marrow aspirate (BM), lymph nodes (LN) and rectal biopsies (RB) were collected longitudinally and at necropsy (Figure 1a).

Bottom Line: In rhesus macaques (RMs), experimental depletion of CD4+ T-cells prior to SIV infection results in higher viremia and emergence of CD4-independent SIV-envelopes.In this study we used the rhesus recombinant anti-CD4 antibody CD4R1 to deplete RM CD4+ T-cells prior to SIVmac251 infection and investigate the sources of the increased viral burden and the lifespan of productively infected cells.We believe these findings have important implications for HIV eradication studies.

View Article: PubMed Central - PubMed

Affiliation: Division of Microbiology & Immunology, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.

ABSTRACT
In rhesus macaques (RMs), experimental depletion of CD4+ T-cells prior to SIV infection results in higher viremia and emergence of CD4-independent SIV-envelopes. In this study we used the rhesus recombinant anti-CD4 antibody CD4R1 to deplete RM CD4+ T-cells prior to SIVmac251 infection and investigate the sources of the increased viral burden and the lifespan of productively infected cells. CD4-depleted animals showed (i) set-point viral load two-logs higher than controls; (ii) macrophages constituting 80% of all SIV vRNA+ cells in lymph node and mucosal tissues; (iii) substantial expansion of pro-inflammatory monocytes; (iv) aberrant activation and infection of microglial cells; and (v) lifespan of productively infected cells significantly longer in comparison to controls, but markedly shorter than previously estimated for macrophages. The net effect of CD4+ T-cell depletion is an inability to control SIV replication and a shift in the tropism of infected cells to macrophages, microglia, and, potentially, other CD4-low cells which all appear to have a shortened in vivo lifespan. We believe these findings have important implications for HIV eradication studies.

No MeSH data available.


Related in: MedlinePlus