Impact on Genetic Networks in Human Macrophages by a CCR5 Strain of Human Immunodeficiency Virus Type 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) impacts multiple lineages of hematopoietic cells, including lymphocytes and macrophages, either by direct infection or indirectly by perturbations of cell networks, leading to generalized immune deficiency. We designed a study to discover, in primary human macrophages, sentinel genetic targets that are impacted during replication over the course of 7 days by a CCR5-using virus. Expression of mRNA and proteins in virus- or mock-treated macrophages from multiple donors was evaluated. Hierarchical agglomerative cluster analysis grouped into distinct temporal expression patterns >900 known human genes that were induced or repressed at least fourfold by virus. Expression of more than one-third of the genes was induced rapidly by day 2 of infection, while other genes were induced at intermediate (day 4) or late (day 7) time points. More than 200 genes were expressed exclusively in either virus- or mock-treated macrophage cultures, independent of the donor, providing an unequivocal basis to distinguish an effect by virus. HIV-1 altered levels of mRNA and/or protein for diverse cellular programs in macrophages, including multiple genes that can contribute to a transition in the cell cycle from G1 to G2/M, in contrast to expression in mock-treated macrophages of genes that maintain G0/G1. Virus treatment activated mediators of cell cycling, including PP2A, which is impacted by Vpr, as well as GADD45 and BRCA1, potentially novel targets for HIV-1. The results identify interrelated programs conducive to optimal HIV-1 replication and expression of genes that can contribute to macrophage dysfunction.

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Proteomic Studies Reveal Coordinated Changes in T-Cell Expression Patterns upon Infection with Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.01819-07 ◽

2008 ◽

Vol 82 (9) ◽

pp. 4320-4330 ◽

Cited By ~ 62

Author(s):

Jeffrey H. Ringrose ◽

Rienk E. Jeeninga ◽

Ben Berkhout ◽

Dave Speijer

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Intracellular Transport ◽

Expression Patterns ◽

Immunodeficiency Virus ◽

Cell Expression ◽

The Impact ◽

Hiv 1

ABSTRACT We performed an extensive two-dimensional differential in-gel electrophoresis proteomic analysis of the cellular changes in human T cells upon human immunodeficiency virus type 1 (HIV-1) infection. We detected 2,000 protein spots, 15% of which were differentially expressed at peak infection. A total of 93 proteins that changed in relative abundance were identified. Of these, 27 were found to be significantly downregulated and 66 were upregulated at peak HIV infection. Early in infection, only a small group of proteins was changed. A clear and consistent program of metabolic rerouting could be seen, in which glycolysis was downregulated and mitochondrial oxidation enhanced. Proteins that participate in apoptotic signaling were also significantly influenced. Apart from these changes, the virus also strongly influenced levels of proteins involved in intracellular transport. These and other results are discussed in light of previous microarray and proteomic studies regarding the impact of HIV-1 infection on cellular mRNA and protein content.

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Bispecific Antibody Targeting of Human Immunodeficiency Virus Type 1 (HIV-1) Glycoprotein 41 to Human Macrophages through the Fe IgG Receptor I Mediates Neutralizing Effects in HIV-1 Infection

The Journal of Infectious Diseases ◽

10.1093/infdis/166.1.93 ◽

1992 ◽

Vol 166 (1) ◽

pp. 93-99 ◽

Cited By ~ 22

Author(s):

A. Mabondzo ◽

P. Aussage ◽

J. Bartholeyns ◽

R. Le Naour ◽

H. Raoul ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Bispecific Antibody ◽

Human Macrophages ◽

Immunodeficiency Virus ◽

Antibody Targeting ◽

Hiv 1

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Human Immunodeficiency Virus Type 1: Resistance to Nucleoside Analogues and Replicative Capacity in Primary Human Macrophages

Journal of Virology ◽

10.1128/jvi.01620-06 ◽

2007 ◽

Vol 81 (9) ◽

pp. 4540-4550 ◽

Cited By ~ 18

Author(s):

Danielle Perez-Bercoff ◽

Sébastien Wurtzer ◽

Séverine Compain ◽

Henri Benech ◽

François Clavel

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Replicative Capacity ◽

Resistance Mutations ◽

Cell Systems ◽

Human Macrophages ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Antiretroviral treatment failure is associated with the emergence of resistant human immunodeficiency virus type 1 (HIV-1) populations which often express altered replicative capacity (RC). The resistance and RC of clinical HIV-1 strains, however, are generally assayed using activated peripheral blood mononuclear cells (PBMC) or tumor cell lines. Because of their high proliferation rate and concurrent high deoxynucleoside triphosphate (dNTP) content, both resistance and RC alterations might be misestimated in these cell systems. We have evaluated the resistance of HIV-1 clones expressing a variety of RT resistance mutations in primary human macrophages using a single cycle system. Our experiments indicate that d4T, ddI, and 3TC are more potent in macrophages than in HeLa-derived P4 tumor cells. Mutant viruses bearing thymidine analogue mutations (TAMs) or the K65R mutation had similar resistance levels in the two cell types. Strikingly, however, the M184V mutant, although fully resistant to 3TC in P4 cells, maintained some susceptibility to 3TC in macrophages from 8 of 11 donors. Using the same system, we found that the impact of resistance mutations on HIV RC was minimal in activated PBMC and in P4 cells. In contrast, mutant viruses exhibited strongly impaired RC relative to the wild type (WT) in macrophages, with the following RC order: WT > two TAMs > four TAMs = M184V > K65R. In undifferentiated monocytes, WT virus replication could be detected in three of six donors, but replication of all mutant viruses remained undetectable. Altogether, our results confirm that nucleoside reverse transcriptase inhibitors (NRTIs) are powerful antiviral agents in differentiated macrophages, reveal that HIV resistance to some NRTIs may be less efficient in these cells, and indicate that resistance-associated loss of RC is more pronounced in macrophages than in high-dNTP content cell systems.

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Virological Consequences of Early Events following Cell-Cell Contact between Human Immunodeficiency Virus Type 1-Infected and Uninfected CD4+ Cells

Journal of Virology ◽

10.1128/jvi.00695-08 ◽

2008 ◽

Vol 82 (16) ◽

pp. 7773-7789 ◽

Cited By ~ 26

Author(s):

Eliana Ruggiero ◽

Roberta Bona ◽

Claudia Muratori ◽

Maurizio Federico

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Fluorescent Protein ◽

Cell Contact ◽

Target Cells ◽

Immunodeficiency Virus ◽

Virus Expression ◽

Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-infected cells transmit viral products to uninfected CD4+ cells very rapidly. However, the natures of the transmitted viral products and the mechanism of transmission, as well as the relative virological consequences, have not yet been fully clarified. We studied the virological events occurring a few hours after contact between HIV-1-infected and uninfected CD4+ cells using a coculture cell system in which the virus expression in target cells could be monitored through the induction of a green fluorescent protein reporter gene driven by HIV-1 long terminal repeats. Within 16 h of coculture, we observed two phenomena not related to the cell-free virus infection, i.e., the formation of donor-target cell fusions and a fusion-independent internalization of viral particles likely occurring at least in part through intercellular connections. Both events depended on the expression of Env and CD4 in donor and target cells, respectively, whereas the HIV-1 internalization required clathrin activity in target cells. Importantly, both phenomena were also observed in cocultures of primary CD4+ lymphocytes, while primary macrophages supported only HIV-1 endocytosis. By investigating the virological consequences of these events, we noticed that while fused cells released infectious HIV-1 particles, albeit with reduced efficiency compared with donor cells, no virus expression was detectable upon HIV-1 endocytosis in target cells. In sum, the HIV-1 transmission following contact between an HIV-1-infected and an uninfected CD4+ cell can occur through different mechanisms, leading to distinguishable virological outcomes.

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