Myeloid and CD4 T Cells Comprise the Latent Reservoir in Antiretroviral Therapy-Suppressed SIVmac251-Infected Macaques

Celina M. Abreu, Rebecca Terilli Veenhuis, Claudia R. Avalos, Shelby Graham, Daymond R. Parrilla, Edna A. Ferreira, Suzanne E. Queen, Erin N. Shirk, Brandon T. Bullock, Ming Li, Kelly Pate, Sarah Beck, Lisa Mangus, Joseph L Mankowski, Feilim Mac Gabhann, Shelby L. O'Connor, Lucio Gama, Janice E Clements

Research output: Contribution to journalArticle

Abstract

Human immunodeficiency virus (HIV) eradication or long-term suppression in the absence of antiretroviral therapy (ART) requires an understanding of all viral reservoirs that could contribute to viral rebound after ART interruption. CD4 T cells (CD4s) are recognized as the predominant reservoir in HIV type 1 (HIV-1)-infected individuals. However, macrophages are also infected by HIV-1 and simian immunodeficiency virus (SIV) during acute infection and may persist throughout ART, contributing to the size of the latent reservoir. We sought to determine whether tissue macrophages contribute to the SIVmac251 reservoir in suppressed macaques. Using cell-specific quantitative viral outgrowth assays (CD4-QVOA and MΦ-QVOA), we measured functional latent reservoirs in CD4s and macrophages in ART-suppressed SIVmac251-infected macaques. Spleen, lung, and brain in all suppressed animals contained latently infected macrophages, undetectable or low-level SIV RNA, and detectable SIV DNA. Silent viral genomes with potential for reactivation and viral spread were also identified in blood monocytes, although these cells might not be considered reservoirs due to their short life span. Additionally, virus produced in the MΦ-QVOA was capable of infecting healthy activated CD4s. Our results strongly suggest that functional latent reservoirs in CD4s and macrophages can contribute to viral rebound and reestablishment of productive infection after ART interruption. These findings should be considered in the design and implementation of future HIV cure strategies.IMPORTANCE This study provides further evidence that the latent reservoir is comprised of both CD4+ T cells and myeloid cells. The data presented here suggest that CD4+ T cells and macrophages found throughout tissues in the body can contain replication-competent SIV and contribute to rebound of the virus after treatment interruption. Additionally, we have shown that monocytes in blood contain latent virus and, though not considered a reservoir themselves due to their short life span, could contribute to the size of the latent reservoir upon entering the tissue and differentiating into long-lived macrophages. These new insights into the size and location of the SIV reservoir using a model that is heavily studied in the HIV field could have great implications for HIV-infected individuals and should be taken into consideration with the development of future HIV cure strategies.

Original languageEnglish (US)
JournalmBio
Volume10
Issue number4
DOIs
StatePublished - Aug 20 2019

Fingerprint

Macaca
Simian Immunodeficiency Virus
Macrophages
T-Lymphocytes
HIV
Viruses
Therapeutics
HIV-1
Monocytes
Viral Genome
Myeloid Cells
Infection
Spleen
RNA
Lung
DNA
Brain

Keywords

  • HIV
  • latency
  • macrophages
  • monocytes
  • SIV

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Myeloid and CD4 T Cells Comprise the Latent Reservoir in Antiretroviral Therapy-Suppressed SIVmac251-Infected Macaques. / Abreu, Celina M.; Terilli Veenhuis, Rebecca; Avalos, Claudia R.; Graham, Shelby; Parrilla, Daymond R.; Ferreira, Edna A.; Queen, Suzanne E.; Shirk, Erin N.; Bullock, Brandon T.; Li, Ming; Pate, Kelly; Beck, Sarah; Mangus, Lisa; Mankowski, Joseph L; Mac Gabhann, Feilim; O'Connor, Shelby L.; Gama, Lucio; Clements, Janice E.

In: mBio, Vol. 10, No. 4, 20.08.2019.

Research output: Contribution to journalArticle

Abreu, Celina M. ; Terilli Veenhuis, Rebecca ; Avalos, Claudia R. ; Graham, Shelby ; Parrilla, Daymond R. ; Ferreira, Edna A. ; Queen, Suzanne E. ; Shirk, Erin N. ; Bullock, Brandon T. ; Li, Ming ; Pate, Kelly ; Beck, Sarah ; Mangus, Lisa ; Mankowski, Joseph L ; Mac Gabhann, Feilim ; O'Connor, Shelby L. ; Gama, Lucio ; Clements, Janice E. / Myeloid and CD4 T Cells Comprise the Latent Reservoir in Antiretroviral Therapy-Suppressed SIVmac251-Infected Macaques. In: mBio. 2019 ; Vol. 10, No. 4.
@article{55fc8068683a42d0b3cf369dd142eabf,
title = "Myeloid and CD4 T Cells Comprise the Latent Reservoir in Antiretroviral Therapy-Suppressed SIVmac251-Infected Macaques",
abstract = "Human immunodeficiency virus (HIV) eradication or long-term suppression in the absence of antiretroviral therapy (ART) requires an understanding of all viral reservoirs that could contribute to viral rebound after ART interruption. CD4 T cells (CD4s) are recognized as the predominant reservoir in HIV type 1 (HIV-1)-infected individuals. However, macrophages are also infected by HIV-1 and simian immunodeficiency virus (SIV) during acute infection and may persist throughout ART, contributing to the size of the latent reservoir. We sought to determine whether tissue macrophages contribute to the SIVmac251 reservoir in suppressed macaques. Using cell-specific quantitative viral outgrowth assays (CD4-QVOA and MΦ-QVOA), we measured functional latent reservoirs in CD4s and macrophages in ART-suppressed SIVmac251-infected macaques. Spleen, lung, and brain in all suppressed animals contained latently infected macrophages, undetectable or low-level SIV RNA, and detectable SIV DNA. Silent viral genomes with potential for reactivation and viral spread were also identified in blood monocytes, although these cells might not be considered reservoirs due to their short life span. Additionally, virus produced in the MΦ-QVOA was capable of infecting healthy activated CD4s. Our results strongly suggest that functional latent reservoirs in CD4s and macrophages can contribute to viral rebound and reestablishment of productive infection after ART interruption. These findings should be considered in the design and implementation of future HIV cure strategies.IMPORTANCE This study provides further evidence that the latent reservoir is comprised of both CD4+ T cells and myeloid cells. The data presented here suggest that CD4+ T cells and macrophages found throughout tissues in the body can contain replication-competent SIV and contribute to rebound of the virus after treatment interruption. Additionally, we have shown that monocytes in blood contain latent virus and, though not considered a reservoir themselves due to their short life span, could contribute to the size of the latent reservoir upon entering the tissue and differentiating into long-lived macrophages. These new insights into the size and location of the SIV reservoir using a model that is heavily studied in the HIV field could have great implications for HIV-infected individuals and should be taken into consideration with the development of future HIV cure strategies.",
keywords = "HIV, latency, macrophages, monocytes, SIV",
author = "Abreu, {Celina M.} and {Terilli Veenhuis}, Rebecca and Avalos, {Claudia R.} and Shelby Graham and Parrilla, {Daymond R.} and Ferreira, {Edna A.} and Queen, {Suzanne E.} and Shirk, {Erin N.} and Bullock, {Brandon T.} and Ming Li and Kelly Pate and Sarah Beck and Lisa Mangus and Mankowski, {Joseph L} and {Mac Gabhann}, Feilim and O'Connor, {Shelby L.} and Lucio Gama and Clements, {Janice E}",
year = "2019",
month = "8",
day = "20",
doi = "10.1128/mBio.01659-19",
language = "English (US)",
volume = "10",
journal = "mBio",
issn = "2161-2129",
publisher = "American Society for Microbiology",
number = "4",

}

TY - JOUR

T1 - Myeloid and CD4 T Cells Comprise the Latent Reservoir in Antiretroviral Therapy-Suppressed SIVmac251-Infected Macaques

AU - Abreu, Celina M.

AU - Terilli Veenhuis, Rebecca

AU - Avalos, Claudia R.

AU - Graham, Shelby

AU - Parrilla, Daymond R.

AU - Ferreira, Edna A.

AU - Queen, Suzanne E.

AU - Shirk, Erin N.

AU - Bullock, Brandon T.

AU - Li, Ming

AU - Pate, Kelly

AU - Beck, Sarah

AU - Mangus, Lisa

AU - Mankowski, Joseph L

AU - Mac Gabhann, Feilim

AU - O'Connor, Shelby L.

AU - Gama, Lucio

AU - Clements, Janice E

PY - 2019/8/20

Y1 - 2019/8/20

N2 - Human immunodeficiency virus (HIV) eradication or long-term suppression in the absence of antiretroviral therapy (ART) requires an understanding of all viral reservoirs that could contribute to viral rebound after ART interruption. CD4 T cells (CD4s) are recognized as the predominant reservoir in HIV type 1 (HIV-1)-infected individuals. However, macrophages are also infected by HIV-1 and simian immunodeficiency virus (SIV) during acute infection and may persist throughout ART, contributing to the size of the latent reservoir. We sought to determine whether tissue macrophages contribute to the SIVmac251 reservoir in suppressed macaques. Using cell-specific quantitative viral outgrowth assays (CD4-QVOA and MΦ-QVOA), we measured functional latent reservoirs in CD4s and macrophages in ART-suppressed SIVmac251-infected macaques. Spleen, lung, and brain in all suppressed animals contained latently infected macrophages, undetectable or low-level SIV RNA, and detectable SIV DNA. Silent viral genomes with potential for reactivation and viral spread were also identified in blood monocytes, although these cells might not be considered reservoirs due to their short life span. Additionally, virus produced in the MΦ-QVOA was capable of infecting healthy activated CD4s. Our results strongly suggest that functional latent reservoirs in CD4s and macrophages can contribute to viral rebound and reestablishment of productive infection after ART interruption. These findings should be considered in the design and implementation of future HIV cure strategies.IMPORTANCE This study provides further evidence that the latent reservoir is comprised of both CD4+ T cells and myeloid cells. The data presented here suggest that CD4+ T cells and macrophages found throughout tissues in the body can contain replication-competent SIV and contribute to rebound of the virus after treatment interruption. Additionally, we have shown that monocytes in blood contain latent virus and, though not considered a reservoir themselves due to their short life span, could contribute to the size of the latent reservoir upon entering the tissue and differentiating into long-lived macrophages. These new insights into the size and location of the SIV reservoir using a model that is heavily studied in the HIV field could have great implications for HIV-infected individuals and should be taken into consideration with the development of future HIV cure strategies.

AB - Human immunodeficiency virus (HIV) eradication or long-term suppression in the absence of antiretroviral therapy (ART) requires an understanding of all viral reservoirs that could contribute to viral rebound after ART interruption. CD4 T cells (CD4s) are recognized as the predominant reservoir in HIV type 1 (HIV-1)-infected individuals. However, macrophages are also infected by HIV-1 and simian immunodeficiency virus (SIV) during acute infection and may persist throughout ART, contributing to the size of the latent reservoir. We sought to determine whether tissue macrophages contribute to the SIVmac251 reservoir in suppressed macaques. Using cell-specific quantitative viral outgrowth assays (CD4-QVOA and MΦ-QVOA), we measured functional latent reservoirs in CD4s and macrophages in ART-suppressed SIVmac251-infected macaques. Spleen, lung, and brain in all suppressed animals contained latently infected macrophages, undetectable or low-level SIV RNA, and detectable SIV DNA. Silent viral genomes with potential for reactivation and viral spread were also identified in blood monocytes, although these cells might not be considered reservoirs due to their short life span. Additionally, virus produced in the MΦ-QVOA was capable of infecting healthy activated CD4s. Our results strongly suggest that functional latent reservoirs in CD4s and macrophages can contribute to viral rebound and reestablishment of productive infection after ART interruption. These findings should be considered in the design and implementation of future HIV cure strategies.IMPORTANCE This study provides further evidence that the latent reservoir is comprised of both CD4+ T cells and myeloid cells. The data presented here suggest that CD4+ T cells and macrophages found throughout tissues in the body can contain replication-competent SIV and contribute to rebound of the virus after treatment interruption. Additionally, we have shown that monocytes in blood contain latent virus and, though not considered a reservoir themselves due to their short life span, could contribute to the size of the latent reservoir upon entering the tissue and differentiating into long-lived macrophages. These new insights into the size and location of the SIV reservoir using a model that is heavily studied in the HIV field could have great implications for HIV-infected individuals and should be taken into consideration with the development of future HIV cure strategies.

KW - HIV

KW - latency

KW - macrophages

KW - monocytes

KW - SIV

UR - http://www.scopus.com/inward/record.url?scp=85071551022&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071551022&partnerID=8YFLogxK

U2 - 10.1128/mBio.01659-19

DO - 10.1128/mBio.01659-19

M3 - Article

C2 - 31431552

AN - SCOPUS:85071551022

VL - 10

JO - mBio

JF - mBio

SN - 2161-2129

IS - 4

ER -