indinavir-sulfate and Cryptococcosis

In this study, we analyzed the possibility that Indinavir (IDV), a well-known protease inhibitor (PI) used in highly active antiretroviral therapy, could affect immune response against the opportunistic fungus Cryptococcus neoformans. In particular, the quality of dendritic cell (DC) response was analyzed. The results reported here show that IDV treatment induces an expansion of DC with CD8alpha phenotype in spleens of infected hosts. Splenic CD11c+ DC expressed elevated costimulatory molecules such as CD40 and CD80, showed an increased expression of mRNA for proinflammatory cytokines, and secreted abundant IL-12. Integration of all aforementioned regulatory effects results in development of an efficient, T cell-protective response that reflects a consistent reduction in fungus colonization at a cerebral level. These results could help to elucidate the immunoregulatory activity of PI and point out the beneficial effects of IDV in regulating DC functions and antifungal activity. Therefore, although new PI are being introduced in the clinical setting, nevertheless, given its low cost and proven efficacy, IDV could still be considered a potential key compound in the treatment of HIV in resource-limited settings.

Topics: Animals; Antifungal Agents; B7-1 Antigen; CD40 Antigens; CD8 Antigens; Cryptococcosis; Cryptococcus neoformans; Dendritic Cells; Female; Flow Cytometry; HIV Protease Inhibitors; Indinavir; Mice; Mice, Inbred BALB C

A previous paper demonstrated that indinavir affects the virulence of Cryptococcus neoformans, thereby rendering the fungus more susceptible to killing by natural effector cells. This study demonstrates that inoculation of immunosuppressed mice with C. neoformans previously exposed to indinavir, in comparison to untreated C. neoformans, results in: (i) a more pronounced secretion of interleukin-12 by splenic dendritic cells; (ii) reduction of CD14 and Fc gammaRs expression on splenic dendritic cells, and upregulation of CD86 and CD40 molecules; (iii) enhancement of interferon-y and interleukin-2 production by splenic T cells and increase of their proliferation in response to fungal antigens; and (iv) survival from an otherwise lethal challenge, correlated with a drastic decrease in colony forming units from brain and liver. In conclusion, these data indicate that indinavir interaction with C. neoformans could be beneficial because of its direct influence on fungal virulence and blunting of the deleterious effects exerted by C. neoformans on host immune response. Thus, indinavir could be crucial in addressing the outcome of cryptococcosis in immunocompromised hosts.

Topics: Animals; B7-2 Antigen; CD4-Positive T-Lymphocytes; CD40 Antigens; Cryptococcosis; Cryptococcus neoformans; Dendritic Cells; Female; HIV Protease Inhibitors; Immunocompromised Host; Indinavir; Interferon-gamma; Interleukin-12; Interleukin-2; Lipopolysaccharide Receptors; Mice; Mice, Inbred BALB C; Nitric Oxide; Receptors, IgG

To analyse the characteristics of opportunistic infections in patients receiving highly active antiretroviral treatment (HAART).. A retrospective study performed in seven hospitals, included all patients starting treatment by ritonavir or indinavir between 26 March and 31 December 1996. Patients were evaluated for the development of AIDS-defining events. Clinical evaluation, plasma HIV-1 RNA quantification, CD4 cell count were recorded at baseline and at the onset of the event.. Four hundred and eighty-six patients were included: 44.2% had a CD4 cell count below 50 x 10(6) cells/l. Fifty clinical events were recorded in 46 patients with a mean follow-up of 6.1 months, of which 34 events (68%) were observed during the first 2 months of HAART. Eighteen of these occurred despite a reduction of viral load by at least 1.5 log10) and a 100% increase of the CD4 cell count compared with that at the onset of the event, corresponding to 11 cytomegalovirus infections, five mycobacterial infections, one case of cryptococcosis, and one case of Varicella-Zoster virus-related acute retinal necrosis. Among the 16 events observed after the second month, six occurred despite a marked biological improvement, corresponding to a recurrence in five of six patients who had stopped their maintenance therapy. Events were one cytomegalovirus infection, two mycobacterial infections, one episode of oesophageal candidiasis and one cryptococcal meningitis.. In patients at high risk of developing an opportunistic infection prior to the institution of a HAART regimen, prophylaxis should not be discontinued during the first 2 months of treatment, and maintenance therapy should be carried on despite a significant increase in the CD4 cell count.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Candidiasis; CD4 Lymphocyte Count; Cryptococcosis; Cytomegalovirus Infections; Disease Progression; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Hospitals, University; Humans; Indinavir; Mycobacterium Infections; Pneumonia, Pneumocystis; Retrospective Studies; Ritonavir; RNA, Viral; Toxoplasmosis, Cerebral; Viral Load