Showing papers by "Andrea Cossarizza published in 2004"

Antiretroviral nucleoside and nucleotide analogues and mitochondria.

Abstract: Mitochondria are the key organelles in energy production in all human cells except erythrocytes. Energy, in the form of ATP, is produced through the highly efficient oxidative phosphorylation pathway. Additionally, mitochondria perform a range of other biological functions and carry a number of factors involved in cell apoptosis. Both HIV infection and antiretroviral nucleoside analogues (nucleoside reverse transcriptase inhibitors; NRTI) are known to affect mitochondrial DNA content and other aspects of mitochondrial function. A number of important clinical events occurring in individuals with HIV infection and on antiretroviral therapy have been linked to mitochondrial injury and dysfunction. In vitro studies have demonstrated that NRTI may differ in their effects on mitochondria and may affect mitochondria in different cell lines in different ways. This is likely to influence the clinical syndromes associated with toxicity to these agents. Dideoxy-NRTI have the greatest affinity for mitochondrial DNA polymerase-a, the enzyme responsible for mitochondrial DNA replication, whereas other nucleoside analogues may influence mitochondrial function also through other mechanisms. These differences may be important in choosing techniques to evaluate the impact of antiretroviral agents on mitochondria.

Discontinuation of Maintenance Therapy for Cryptococcal Meningitis in Patients with AIDS Treated with Highly Active Antiretroviral Therapy: An International Observational Study

Abstract: We conducted a retrospective, multicenter study evaluating the safety of discontinuing maintenance therapy for cryptococcal meningitis after immune reconstitution. Inclusion criteria were a previous definitive diagnosis of cryptococcal meningitis, a CD4 cell count of >100 cells/microL while receiving highly active antiretroviral therapy (HAART), and the subsequent discontinuation of maintenance therapy for cryptococcal meningitis. The primary end point was relapse of cryptococcal disease. As of July 2002, 100 patients were enrolled. When maintenance therapy was discontinued, the median CD4 cell count was 259 cells/microL and the median plasma virus load was 100 cells/microL and a positive serum cryptococcal antigen test result during the recurrent episode. In conclusion, discontinuation of maintenance therapy for cryptococcal meningitis is safe if the CD4 cell count increases to >100 cells/microL while receiving HAART. Recurrent cryptococcal infection should be suspected in patients whose serum cryptococcal antigen test results revert back to positive after discontinuation of maintenance therapy.

Highly active antiretroviral therapy restores CD4+ Vbeta T-cell repertoire in patients with primary acute HIV infection but not in treatment-naive HIV+ patients with severe chronic infection.

Abstract: In drug-naive HIV + patients, we analyzed the effects of highly active antiretroviral therapy (HAART) on the reconstitution of the T-cell receptor (TCR) repertoire. We followed 2 groups of patients for 1 year: 18 individuals who experienced acute HIV infection and 24 patients who had HIV infection for many years but never took HAART. They were compared with 10 healthy controls who were longitudinally analyzed for the same period. We performed cytofluorometric analysis of the Vβ TCR repertoire and detected the clonality of different Vβ families by the spectratyping method. A new statistical approach based on the use of mixed models was then employed to analyze the data. Before the beginning of therapy, the repertoire of patients with acute or chronic infection was significantly different from that of healthy controls. After therapy, patients with acute HIV infection showed an improvement of the repertoire among either CD4 + or CD8 + T lymphocytes. Conversely, patients with chronic infection were capable of changing their repertoire among CD8 + but not CD4 + T lymphocytes. Our results indicate that HAART can restore the T-cell repertoire in individuals whose immune system is not severely compromised by the infection.

Balanced regulation of mRNA production for Fas and Fas ligand in lymphocytes from centenarians: how the immune system starts its second century.

Abstract: Background— The functionality of the immune system during aging is crucial for protection against the most common age-related diseases. Apoptosis plays a central role in the senescence of the immune system, as evidenced by the increased plasma membrane expression of a key molecule like Fas protein. We analyzed the mRNA levels of different forms of Fas (total [tFas] and membrane [mFas]) and of its ligand (FasL) in peripheral blood lymphocytes from centenarians, the best example of successful aging, who were compared with young and middle-aged donors. Methods and Results— Using real-time polymerase chain reaction, we quantified mRNA for different forms of Fas and for FasL. In resting lymphocytes, mRNA for tFas, but not for mFas, significantly increases with age, whereas FasL mRNA significantly decreases. In vitro production of Fas/FasL mRNA after different stimuli was similar in cells from the 3 groups. Even if the percentage of Fas+ cells was higher than in the other groups, peripheral blood lymphocytes fr...

The human immunodeficiency virus (HIV) protease inhibitor indinavir directly affects the opportunistic fungal pathogen Cryptococcus neoformans

Abstract: Highly active antiretroviral therapy (HAART), that includes human immunodeficiency virus (HIV) protease inhibitors (PIs), has been remarkably efficacious including against some opportunistic infections. In this report we investigated the effect(s) of the PI indinavir on protease activity by Cryptococcus neoformans, an opportunistic fungal pathogen responsible for recurrent meningoencephalitis in AIDS patients. Indinavir was also tested for potential effects on other parameters, such as fungal viability, growth ability and susceptibility to immune effector cells. It was found that indinavir impaired cryptococcal protease activity in a time- and dose-dependent fashion. The phenomenon was similarly detectable in ATCC/laboratory strains and clinical isolates. C. neoformans growth rate was also significantly reduced upon exposure to indinavir, while fungal viability was not affected and mitochondrial toxicity not detected. Furthermore, as assessed by an in vitro infection model, indinavir significantly and consistently augmented C. neoformans susceptibility to microglial cell-mediated phagocytosis and killing. Overall, by providing the first evidence that indinavir directly affects C. neoformans, these data add new in vitro insights on the wide-spectrum efficacy of PIs, further arguing for the clinical relevance of HAART against opportunistic infections in AIDS.

Decreased apoptosis of bone marrow progenitor cells in HIV-1-infected patients during highly active antiretroviral therapy.

Abstract: Impaired haematopoiesis during HIV-1 infection may be caused by the overproduction of inflammatory cytokines by immune cells at the bone marrow level inducing Fas-mediated apoptosis of stem progenitors. In this study, we evaluated the effects of highly active antiretroviral therapy on apoptosis of CD34+ stem cells derived from the bone marrow of HIV-1-infected patients, and observed decreased Fas expression on progenitor cells, in parallel with the diminution of TNF-alpha levels and the amelioration of clonogenic parameters.

HIV: no PUMA no death?

Abstract: The presence of syncytia-inducing (SI) virus, and the formation of multinucleated cells (syncytia) is supposed to play a major role in the progression of infection with the human immunodeficiency virus (HIV). SI viruses, which use the chemokine receptor CXCR4 to infect cells expressing the CD4 molecule (the main receptor for HIV, present on T-helper lymphocytes, monocytes and macrophages), are found more frequently in patients with an advanced stage of the disease than the non-syncytia-inducing (NSI) type, which are usually isolated in the asymptomatic period of the infection. SI HIV isolates have a greater capacity to kill infected cells in culture than do NSI strains, and the switch from NSI to SI is considered a marker of disease progression and an unfavourable prognostic sign. Formation of syncytia causes cell death with features of either apoptosis or necrosis. As far as lymphocytes or monocytes are concerned, syncytia are formed by the fusion of infected with uninfected CD4+ cells: in culture, their formation is one of the first signs of HIV infection of peripheral blood mononuclear cells (PBMC), appearing 2–3 days after adding viral particles or infected biological material (such as cells or plasma). In T-cell lines such as MT-2, the formation of syncytia can occur as early as 2 h after the infection.1 Cell fusion is temperature-dependent and does not require DNA, RNA or protein synthesis. It involves carbohydrates and lipids present on the cell membrane and depends on CD4 and the HIV gp120 and gp41 envelope proteins.2

Complementary and alternative medicine during HIV infection.

Abstract: According to the Joint United Nations Program of HIV/AIDS (UNAIDS) and the World Health Organization (WHO) (Joint United Nations Program of HIV/AIDS, 2001), as of the end of 2001, there were about 40 million adults and children living with human immunod-eficiency virus (HIV) infection. This total does not include the 20 million people around the world who already died of AIDS. Of the 40 million currently alive, 37.2 are adults, 17.6 are women, and more than 2.7 are children. In 2001, there were 5 million new cases of HIV infection in the world, and 3 million AIDS related deaths. The large majority (almost three quarters) live in Sub-Saharan Africa where the prevalence rate of the infection among adults is 8.4%; more than 55% of infected individuals are women. The second major pocket of HIV infection is in South and Southeast Asia, with more than 6 million people infected. In North America where the epidemic was first described, there are 940,000 individuals who are HIV- , and in Western Europe, 540,000. Furthermore, South America, China, and East-ern Europe are characterized by a rapid increase in infection rates. These dramatic numbers clearly indicate that the fight against HIV/AIDS is an absolute health, social, economical and political priority in all parts of the world.

Complementary and Alternative Medicine During HIV Infection

Abstract: According to the Joint United Nations Program of HIV/AIDS (UNAIDS) and the World Health Organization (WHO) (Joint United Nations Program of HIV/AIDS, 2001), as of the end of 2001, there were about 40 million adults and children living with human immunod-eficiency virus (HIV) infection. This total does not include the 20 million people around the world who already died of AIDS. Of the 40 million currently alive, 37.2 are adults, 17.6 are women, and more than 2.7 are children. In 2001, there were 5 million new cases of HIV infection in the world, and 3 million AIDS related deaths. The large majority (almost three quarters) live in Sub-Saharan Africa where the prevalence rate of the infection among adults is 8.4%; more than 55% of infected individuals are women. The second major pocket of HIV infection is in South and Southeast Asia, with more than 6 million people infected. In North America where the epidemic was first described, there are 940,000 individuals who are HIV- , and in Western Europe, 540,000. Furthermore, South America, China, and East-ern Europe are characterized by a rapid increase in infection rates. These dramatic numbers clearly indicate that the fight against HIV/AIDS is an absolute health, social, economical and political priority in all parts of the world.