Biomedical subjects

Secondo Sonza

Publications and source records attributed to Secondo Sonza.

6 recordsLinked to original sources

PubMed2006

SerpinB2 is an inducible host factor involved in enhancing HIV-1 transcription and replication.

The serine protease inhibitor SerpinB2 (plasminogen activator inhibitor-2) is a major product of activated monocytes and macrophages and is substantially induced during most inflammatory processes. Distinct from its widely described extracellular role as an inhibitor of urokinase plasminogen activator, SerpinB2 has recently been shown to have an intracellular role as a retinoblastoma protein (Rb)-binding protein that inhibits Rb degradation. Here we show that HIV-1 infection and gp120 treatment of human peripheral blood mononuclear cells resulted in induction of SerpinB2. Furthermore, SerpinB2 expression in THP-1 monocyte/macrophage, Jurkat T, and HeLa cell lines increased replication of HIV-1 and enhanced transcription from the HIV-1 long terminal repeat (LTR) promoter by 3-10-fold. Increased HIV-1 gene expression and transcription was also observed in activated macrophages from SerpinB2+/+ mice compared with macrophages from SerpinB2-/- mice. The SerpinB2-mediated elevation of Rb protein levels appeared to be responsible for enhancing transcription from the core promoter region of the LTR by relieving HDM2-mediated inhibition of Sp1 and/or by increasing the Sp1/Sp3 expression ratios. This is the first report associating HIV-1 replication with SerpinB2 expression and illustrates that SerpinB2 is a potentially important inducible host factor that significantly promotes HIV-1 replication.

Animals↗

PubMed2006

Normal CD16 expression and phagocytosis of Mycobacterium avium complex by monocytes from a current cohort of HIV-1-infected patients.

Monocyte phenotype and function were measured in whole blood sampled from a current cohort of human immunodeficiency virus (HIV)-infected individuals attending a large, metropolitan, university-affiliated hospital. There was no significant difference in the prevalence of CD16+ monocytes or the capacity of monocytes to ingest heat-killed Mycobacterium avium complex between these individuals and HIV-uninfected control subjects, regardless of viral load, current CD4+ T cell count, nadir CD4+ T cell count, or time since diagnosis of HIV infection. CD16+ monocyte prevalence was, however, elevated in patients not currently receiving antiretroviral therapy. We conclude that HIV type 1 infection in the setting of highly active antiretroviral therapy is associated with normal monocyte function and phenotype.

Anti-HIV Agents↗

PubMed2006

Use of laser capture microdissection to detect integrated HIV-1 DNA in macrophages and astrocytes from autopsy brain tissues.

The importance of astrocytes as a reservoir of human immunodeficiency virus type 1 (HIV-1) in the brain remains elusive. By combining immunohistochemistry, laser capture microdissection, and triple-nested Alu-PCR, we demonstrate integrated HIV-1 in astrocytes and macrophages isolated directly from autopsy brain tissues of HIV-1-infected subjects. The ability of HIV-1 to integrate in terminally differentiated astrocytes suggests a permanent reservoir of provirus in brain that will impact the development and likely success of strategies aimed at eradicating HIV-1.

AIDS Dementia Complex↗

PubMed2005

Mutations that abrogate human immunodeficiency virus type 1 reverse transcriptase dimerization affect maturation of the reverse transcriptase heterodimer.

The specific impact of mutations that abrogate human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) dimerization on virus replication is not known, as mutations shown previously to inhibit RT dimerization also impact Gag-Pol stability, resulting in pleiotropic effects on HIV-1 replication. We have previously characterized mutations at codon 401 in the HIV-1 RT tryptophan repeat motif that abrogate RT dimerization in vitro, leading to a loss in polymerase activity. The introduction of the RT dimerization-inhibiting mutations W401L and W401A into HIV-1 resulted in the formation of noninfectious viruses with reduced levels of both virion-associated and intracellular RT activity compared to the wild-type virus and the W401F mutant, which does not inhibit RT dimerization in vitro. Steady-state levels of the p66 and p51 RT subunits in viral lysates of the W401L and W401A mutants were reduced, but no significant decrease in Gag-Pol was observed compared to the wild type. In contrast, there was a decrease in processing of p66 to p51 in cell lysates for the dimerization-defective mutants compared to the wild type. The treatment of transfected cells with indinavir suggested that the HIV-1 protease contributed to the degradation of virion-associated RT subunits. These data demonstrate that mutations near the RT dimer interface that abrogate RT dimerization in vitro result in the production of replication-impaired viruses without detectable effects on Gag-Pol stability or virion incorporation. The inhibition of RT activity is most likely due to a defect in RT maturation, suggesting that RT dimerization represents a valid drug target for chemotherapeutic intervention.

Codon↗

PubMed2005

Isolation of human immunodeficiency virus type 1 from peripheral blood monocytes.

Human immunodeficiency virus type 1 (HIV-1) can infect circulating peripheral blood monocytes and resting CD4+ T lymphocytes despite sustained suppression of plasma viremia to undetectable levels. These persistently infected cell populations pose a barrier for virus eradication by highly active antiretroviral therapy (HAART), and are a significant reservoir of HIV-1 contributing to viral rebound following cessation or failure of HAART. This chapter provides a protocol for isolating replication-competent HIV-1 from peripheral blood monocytes of HIV-1-infected individuals, including those with sustained plasma HIV-1 RNA levels below 50 copies/mL, by co-culture with CD8-depleted, phytohemagglutinin-activated donor peripheral blood mononuclear cells. In our laboratory, this protocol has the sensitivity to achieve a success rate of positive HIV-1 isolation in approx 70% of cases. The study of HIV-1 strains harbored by peripheral blood monocytes of patients undergoing HAART will contribute to the understanding of viral persistence in cellular reservoirs that impede effective HAART.

CD8 Antigens↗

PubMed2002

Selectively reduced tat mRNA heralds the decline in productive human immunodeficiency virus type 1 infection in monocyte-derived macrophages.

The transcription and splicing of human immunodeficiency virus type 1 (HIV-1) mRNA in primary blood monocyte-derived macrophages (MDM) and CD4(+) peripheral blood lymphocytes (PBL) were compared to determine whether any differences might account for the slower noncytopathic infection of cells of the macrophage lineage. The expression of regulatory mRNAs during acute infection of MDM was delayed by about 12 h compared to that of PBL. In each cell type, an increase in spliced viral mRNAs slightly preceded virus production from the culture. Following the peak of productive infection, there was a proportional decrease in the expression of all regulatory mRNAs detected in PBL. In MDM, a dramatic additional decrease specifically in the tat mRNA species heralded a reduction in virus production. This decline in tat mRNA was reflected by a concomitant decrease in Tat activity in the cells and occurred with the same kinetics irrespective of the age of the cells when infected. Addition of exogenous Tat protein elicited a burst of virus production from persistently infected MDM, suggesting that the decrease in virus production from the cultures is a consequence of the reduction in tat mRNA levels. Our results show that modulation of HIV-1 mRNAs in macrophages during long-term infection, which is dependent on the period of infection rather than cell differentiation or maturation, results in a selective reduction of Tat protein levels at the commencement of a persistent, less productive phase of infection. Determination of the mechanism of this mRNA modulation may lead to novel targets for control of replication in these important viral reservoirs.

Alternative Splicing↗