ALBERT

Description: Although generalized T-cell activation is an important factor in chronic HIV disease pathogenesis, its role in primary infection remains poorly defined. To investigate the effect of immune activation on T-cell changes in subjects with early HIV infection, and to test the hypothesis that an immunologic activation “set point” is established early in the natural history of HIV disease, a prospective cohort of acutely infected adults was performed. The median density of CD38 molecules on CD4+ and CD8+ T cells was measured longitudinally in 68 antiretroviral-untreated individuals and 83 antiretroviral-treated individuals. At study entry, T-cell activation was positively associated with viremia, with CD8+ T-cell activation levels increasing exponentially at plasma HIV RNA levels more than 10 000 copies/mL. Among untreated patients, the level of CD8+ T-cell activation varied widely among individuals but often remained stable within a given individual. CD8+ T-cell activation and plasma HIV RNA levels over time were independently associated with the rate of CD4+ T-cell loss in untreated individuals. These data indicate that immunologic activation set point is established early in HIV infection, and that this set point determines the rate at which CD4+ T cells are lost over time.

Description: Introduction: HIV infected individuals are 17x more likely to receive a diagnoses of Diffuse Large B cell Lymphoma (DLBCL) compared to their uninfected counterparts. Moreover, DLBCL is more aggressive in HIV infected individuals, with up to 70% of patients being primary refractory to chemotherapeutic regimens. However, the molecular pathology driving the aggressive nature of HIV related DLBCL is poorly understood. Here, we have assessed the genomic and transcriptional differences between HIV(+) and HIV(-) DLBCL in order to identify the mechanisms driving the enhanced aggressive and refractory nature of HIV related DLBCL. Methods: A total of 66 cases, including 27 HIV(+) from the AIDS Cancer Specimen Resource Network (https://acsr.ucsf.edu/) and 39 HIV(-) institutional cases were included in this study. Fresh H&Es were reviewed by a hematopathologist to validate diagnosis and determine tumor content. Samples with

Description: Abstract 5205 Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) are the two most common AIDS-defining cancers and significantly contribute to HIV-related deaths. While highly active antiretroviral therapy (HAART) has produce a sharp decline in the incidence of KS and AIDS-related NHL (ARL), HIV-infected patients are still at a high risk for developing these malignancies. Recent studies evaluating HIV-1 DNA in 91 AIDS-related KS cases demonstrated a significant decrease in the prevalence of HIV-1 DNA positive KS cases post-HAART (after 1996; 16.7%) as compared to pre-HAART (before 1996; 45%) corresponding to the decrease in incidence of this cancer since the introduction of HAART. Additionally HIV was more prevalent in sites of visceral KS (51.9%) as compared to skin KS (30.7%). We have recently evaluated the HIV sequence evolution in the context of metastatic ARL and identified lymphoma-specific HIV compartmentalized within tumor sites that was genetically distinct from HIV in non-tumor sites suggesting a specific form of HIV arises within individuals who develop ARL. The goal of this research was to determine the prevalence and quantity of HIV DNA in 119 ARL biopsies representing the entire span of the HIV epidemic (1982–2005). Whole genomic amplification was performed on DNA extracted from three 10um paraffin embedded tissue sections and the presence of HIV-1 DNA was determined by quantitative amplification of the HIV gag gene. Of the 119 cases, 45% contained detectable levels of HIV DNA. The HIV antigen was predominantly localized to macrophages. A subset of the ARL cases in this study contained approximately 1 HIV copy per cell which is extremely high considering previously reported data describing HIV-infected lymph nodes contained approximately 1 HIV copy per 1000 cells. Similar to what was observed for KS, the prevalence of HIV-positive ARLs has decreased in the post-HAART era (39%) when compared to pre-HAART (54%). While the prevalence of HIV-1 DNA positive ARLs declined in the post-HAART era, it was not to the same extent as what was observed for KS. Thus, our data is consistent with a decrease in the incidence of both tumor types in the post-HAART era. The higher prevalence of HIV-1 DNA in visceral sites of KS and lymphoma specific-HIV sequences in sites of metastatic lymphoma suggests that HIV, especially HIV infected macrophages, may play a role in the pathogenesis of KS and ARL disease progression. Disclosures: No relevant conflicts of interest to declare.

Description: Immune dysfunction is known to contribute to lymphomagenesis in the context of immunosuppressive therapy and infection with HIV. The current study was undertaken to test whether low grade but progressive forms of lymphoma, mantle cell lymphoma (MCL) and follicular lymphoma (FL), might be associated with systemic immunologic dysfunction as evaluated by flow cytometry. Because of recent studies suggesting a tumor initiating function for infiltrating macrophages in AIDS lymphoma (Zenger et al, Cancer Research62:5536–42,2002), we investigated the immunophenotype of both monocytes and T cells in blood from patients with recurrent MCL and FL. Heparinized blood was taken from 13 individuals with MCL and 6 with FL, both sets of patients previously treated with an average of 4 cycles of combination chemotherapy +/− Rituxan. No patient had received any therapy during the 3 months prior to the current study. Cell surface antigens CD14, CD16, HLA-DR, CD4, CD8, and CD38 were studied in the two diseases and results were compared to age matched controls. Blood from MCL patients showed an immunophenotypic pattern, similar to blood phenotypes described for patients infected with HIV. The %CD4 population was significantly lower than normal controls (p