**6. Conclusions**

68 Bioinformatics

cell cycle.

7165]

7154]

48518]

65007]

[GO-ID: 7242]

[GO-ID: 51244]

[GO-ID: 6796]

[GO-ID: 6793]

networks a.

Signal transduction [GO-ID:

Cell communication [GO-ID:

Positive regulation of cellular process [GO-ID: 51242]

Biological regulation [GO-ID:

Intracellular signaling cascade

Regulation of cellular process

Phosphate metabolic process

phosphorus metabolic process

**b**. p-Value calculated as an exponential function.

Regulation of biological process [GO-ID: 50791]

Positive regulation of biological process [GO-ID:

in metabolic process and DNA repair process.

could be further classified into two major groups; cell function regulation and signaling of biological process. In contrast HIV-1 infected macrophage gene network was enriched with 10 significant functional categories of a total of 40. The significantly overrepresented categories indicated that this emergent new gene network was composed by genes involved

In this study we simulated at systemic level, the alterations of cellular pathways when HIV provirus integrates into genes by turning them off and produce dysregulation of several local signaling pathways. One of the target gene associated with HIV-1 integration was AKT3, also called PKB, which is a serine/threonine protein kinase family member. It is involved in a wide range of biological processes including cell proliferation, differentiation, apoptosis, stimulating cell growth, and regulating other biological responses (59, 60). Also, it have been identified playing important roles of regulation in the G2/M transition of the

**Normal Network p-value b HIV-1 infected Network p-value b**

3,90E-123 Biopolymer biosynthetic process [GO-ID: 43284]

1,39E-95 Macromolecule biosynthetic process

1,45E-88 alcohol metabolic process [GO-ID:

2,65E-84 Furaldehyde metabolic process [GO-

3,01E-80 Age-dependent response to reactive

cell aging [GO-ID: 1320]

1,40E-86 Maintenance of fidelity during

[GO-ID: 45005]

ID: 33859]

**a**. The description of the gene ontology biological processes and the corresponding gene ontology identifiers are given.

**Table 2.** The top 10 of significant biological process of normal and HIV-1 infected macrophages

[GO-ID: 9059]

6066]

4,63E-120 Metabolic process [GO-ID: 8152] 8,00E-05

1,93E-92 Biosynthetic process [GO-ID: 9058] 2,43E-03

DNA-dependent DNA replication

2,29E-85 Mismatch repair [GO-ID: 6298] 6,24E-03

oxygen species during chronological

3,01E-80 oxidation reduction [GO-ID: 55114] 6,90E-03

6,27E-05

1,40E-03

3,19E-03

6,24E-03

6,68E-03

6,68E-03

We can conclude that a general effect of HIV-1 integrations in macrophages DNA is to disrupt several signaling pathways that control the normal cell homeostasis. Comparison between normal and infected macrophages of top 10 GO function categories showed the dramatic change of one non-infected macrophage whose main cellular functions are devoted to maintain a cell signaling crucial functions, to one infected in which the most important function are macromolecular biosynthetic process, maintenance of fidelity during DNAdependent DNA replication, mismatch repair, age-dependent response to reactive oxygen species during chronological cell aging and oxidation reduction. As HIV infected macrophage is an abnormal reservoir in which the metabolic cascades are altered, it is possible to propose that the metabolism of macrophage adapt to perform survival functions where the apoptotic process is interrupted and a SOS metabolism make that the macrophage change of its life style

*In silico* studies are based upon statistical calculations which permit the drawing of generalizations about a biological process; however since some variables could affecting the *in toto* process, in order to get a real history of Lentivirus integration it would be important to consider that there is another factors, including physiological process and cellular compartments that would be influencing the *in vivo* integration site selection. Some of these are cell-cycle phase, the transcriptional state of the cell, the topology of chromosomal DNA, cell type infected, and presence of co-helper molecules during the PIC complex conformation

By providing these new testable hypotheses we hope that our results will accelerate experimental efforts to define a reliable disturbing in the gene complex relationship by lentivirus integration in PBMC and macrophages which are critical immune cells responsible for a wide range of immune functions and play multifaceted roles in HIV pathogenesis

Systemic Approach to the Genome Integration Process of Human Lentivirus 71

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