Bruce L. Gilliam

Higher Incidence of Acute Kidney Injury With Intravenous Colistimethate Sodium Compared With Polymyxin B in Critically Ill Patients at a Tertiary Care Medical Center

Nephrotoxicity was assessed in 173 critically ill patients receiving intravenous colistin or polymyxin B; it occurred in 60.4% and 41.8%, respectively. Further investigation is necessary to elucidate the reason for the difference in nephrotoxicity observed between the groups and to assess the impact of severity of illness and dosing/administration.

Clinical use of CCR5 inhibitors in HIV and beyond.

Since the discovery of CCR5 as a coreceptor for HIV entry, there has been interest in blockade of the receptor for treatment and prevention of HIV infection. Although several CCR5 antagonists have been evaluated in clinical trials, only maraviroc has been approved for clinical use in the treatment of HIV-infected patients. The efficacy, safety and resistance profile of CCR5 antagonists with a focus on maraviroc are reviewed here along with their usage in special and emerging clinical situations. Despite being approved for use since 2007, the optimal use of maraviroc has yet to be well-defined in HIV and potentially in other diseases. Maraviroc and other CCR5 antagonists have the potential for use in a variety of other clinical situations such as the prevention of HIV transmission, intensification of HIV treatment and prevention of rejection in organ transplantation. The use of CCR5 antagonists may be potentiated by other agents such as rapamycin which downregulate CCR5 receptors thus decreasing CCR5 density. There may even be a role for their use in combination with other entry inhibitors. However, clinical use of CCR5 antagonists may have negative consequences in diseases such as West Nile and Tick-borne encephalitis virus infections. In summary, CCR5 antagonists have great therapeutic potential in the treatment and prevention of HIV as well as future use in novel situations such as organ transplantation. Their optimal use either alone or in combination with other agents will be defined by further investigation.

Plasmablastic lymphoma of the oral cavity: a rapidly progressive lymphoma associated with HIV infection

Plasmablastic lymphoma of the oral cavity is a form of non-Hodgkin lymphoma (NHL) and was first described in 1997. We describe a case of plasmablastic lymphoma in an HIV-infected patient who presented with an expanding oral lesion and symptoms of a toothache. We review all cases of plasmablastic lymphoma that have been reported in the literature. Plasmablastic lymphoma is strongly associated with immunodeficiency, and most particularly, with HIV infection. The pathophysiological origin of plasmablastic lymphoma has not been fully characterised, but the presence of Epstein-Barr virus (EBV) has often been documented in biopsy specimens, supporting a role for EBV in the pathogenesis of this lymphoma. The differential diagnosis for an expanding oral lesion includes both infectious and malignant processes. Biopsy is essential for making a correct and prompt diagnosis. Treatment usually involves chemotherapy, but antiretroviral therapy may also have an important role. Infectious disease clinicians should be aware of this newly described and increasingly encountered lymphoma, since it is prominently associated with immunosuppression and may be mistaken for other entities.

CCR5 density levels on primary CD4 T cells impact the replication and Enfuvirtide susceptibility of R5 HIV-1.

Objective and design:Studies in cell lines have demonstrated that CCR5 coreceptor levels influence the replication efficiency and Enfuvirtide (T-20) susceptibility of R5 HIV-1 strains. At present, however, the role that CCR5 levels on primary CD4 T cells – which are markedly lower than in cell lines and vary only ∼fivefold among most donors – may play in virus replication levels or susceptibility to T-20 is not known. In the present study we evaluated the impact of differences in CCR5 levels among donor CD4 T cells on the infection efficiency and T-20 susceptibility of R5 HIV-1. Methods:CD4 and CCR5 density levels were determined by Quantitative FACS analysis. Virus infectivity assays were conducted in cell lines and primary cells. Associations between coreceptor density, virus replication and T-20 sensitivity were tested using the Spearmans correlation test. Results:We found a positive correlation (r, 0.55; P = 0.011) between CCR5 density levels on primary CD4 T cells and replication of R5 HIV-1. In cell lines expressing physiologically relevant levels of CD4 and CCR5, T-20 was significantly more potent in cells with low CCR5 levels. In addition, T20 50% inhibitory concentrations for R5 HIV-1 replication varied ∼100-fold among primary cells from different donors and they were positively correlated with CCR5 density values (r, 0.84; P = 0.00004). Conclusions:These results suggest that CCR5 density levels in HIV-1 patients may impact the activity of T-20 against R5 strains and that therapeutic approaches to alter CCR5 density may potentiate T-20.

Increased expression of suppressor of cytokine signaling-1 (SOCS-1): A mechanism for dysregulated T helper-1 responses in HIV-1 disease.

Maintenance of Th1 responses and dendritic cell (DC) functions are compromised in HIV-1 infected individuals. To better understand these immune abnormalities, we developed an HIV-1 transgenic (Tg) rat. We report that Tg DCs induce elevated levels of SOCS-1 and secrete decreased IL-12p40 and elevated levels of IL-10 following TLR-4 stimulation by LPS. This leads to further induction of SOCS-1 by IL-10 and decreased IFN-gamma-mediated induction of interferon response factor (IRF)-1 and IL-12Rbeta1 expression in CD4+ T cells and to decreased IL-12-induction of IFN-gamma production by Th1 polarized T cells. We also show that SOCS-1 is elevated in CD4+ T cells from HIV-1 infected progressors, and is correlated with defective induction of IRF-1 following IFN-gamma stimulation, compared with healthy controls and HIV-1 natural viral suppressor (NVS) patients. These results suggest a link between high levels of SOCS-1, defects in innate immunity and adaptive Th1 responses that may be reflected in the loss of Th1 immune competence observed with AIDS patients.

Rapamycin reduces CCR5 mRNA levels in macaques : potential applications in HIV-1 prevention and treatment

G1 cytostatic drugs reduce CCR5 co-receptor expression and enhance the antiviral activity of a CCR5 antagonist in vitro. The administration of rapamycin, a G1 cytostatic agent, to three cynomolgous macaques led to decreased CCR5 messenger RNA expression in peripheral blood mononuclear cells and cervicovaginal tissue. These results support further clinical evaluation of G1 cytostatic agents such as rapamycin targeting the downregulation of CCR5 expression as a strategy for both the prevention and treatment of HIV infection.

Rapamycin Reduces CCR5 Density Levels on CD4 T Cells, and This Effect Results in Potentiation of Enfuvirtide (T-20) against R5 Strains of Human Immunodeficiency Virus Type 1 In Vitro

ABSTRACT The CCR5 chemokine receptor plays a pivotal role in human immunodeficiency virus type 1 (HIV-1) infection. Several studies have suggested that CCR5 density levels in individuals are rate limiting for infection. In addition, CCR5 density levels influence the antiviral activity of the HIV-1 fusion inhibitor enfuvirtide (T-20) against R5 strains. In the present study we demonstrate that rapamycin (RAPA), a drug approved for the treatment of renal transplantation rejection, reduces CCR5 density levels on CD4 T cells and inhibits R5 HIV-1 replication. In addition, RAPA increased the antiviral activity of T-20 against R5 strains of the virus in a cell-cell fusion assay and as shown by quantification of early products of viral reverse transcription. Median-effect analysis of drug interaction between RAPA and T-20 in infectivity assays using donor peripheral blood mononuclear cells demonstrated that the RAPA-T-20 combination is synergistic against R5 strains of HIV-1 and this synergy translates into T-20 dose reductions of up to ∼33-fold. Importantly, RAPA effects on replication levels and T-20 susceptibility of R5 strains of HIV-1 were observed at drug concentrations that did not inhibit cell proliferation. These results suggest that low concentrations of RAPA may potentiate the antiviral activity of T-20 against R5 strains of HIV-1, which are generally present throughout the course of infection and are less sensitive to T-20 inhibition than are X4 strains.

High cancer-related mortality in an urban, predominantly African-American, HIV-infected population.

Objective:To determine mortality associated with a new cancer diagnosis in an urban, predominantly African–American, HIV-infected population. Design:Retrospective cohort study. Methods:All HIV-infected patients diagnosed with cancer between 1 January 2000 and 30 June 2010 were reviewed. Mortality was examined using Kaplan–Meier estimates and Cox proportional hazards models. Results:There were 470 cases of cancer among 447 patients. Patients were predominantly African–American (85%) and male (79%). Non-AIDS-defining cancers (NADCs, 69%) were more common than AIDS-defining cancers (ADCs, 31%). Cumulative cancer incidence increased significantly over the study period. The majority (55.9%) was taking antiretroviral therapy (ART) at cancer diagnosis or started afterward (26.9%); 17.2% never received ART. Stage 3 or 4 cancer was diagnosed in 67%. There were 226 deaths during 1096 person years of follow-up, yielding an overall mortality rate of 206 per 1000 person years. The cumulative mortality rate at 30 days, 1 year, and 2 years was 6.5, 32.2, and 41.4%, respectively. Mortality was similar between patients on ART whether they started before or after the cancer diagnosis but was higher in patients who never received ART. In patients with a known cause of death, 68% were related to progression of the underlying cancer. Conclusion:In a large cohort of urban, predominantly African–American patients with HIV and cancer, many patients presented with late-stage cancer. There was substantial 30-day and 2-year mortality, although ART had a significant mortality benefit. Deaths were most often caused by progression of cancer and not from another HIV-related or AIDS-related event.

Infectious Diseases and the Liver

The liver plays an important role in host defense against invasive microorganisms. The effect of microbial pathogens on the liver can vary greatly, presenting with a wide variety of manifestations from asymptomatic increases in aminotransaminases, acute liver failure, hepatic fibrosis, and cirrhosis. In evaluating the liver manifestations of a potential infectious pathogen, diagnosis of some of the less common infectious pathogens is dependent on a high level of suspicion and recognition of some of the key diagnostic clues. Successful diagnosis can only be accomplished through a careful history, including travel and exposures, physical examination, and appropriate microbiologic studies. This article reviews the involvement of the liver during systemic infections with organisms that are not considered to be primarily hepatotropic.

Two independent epidemics of HIV in Maryland.

Background:HIV-1 subtype B virus is the predominant subtype in HIV-infected individuals in the United States. However, increasing evidence suggests that prevalence of non-B subtypes may be on the rise in the West, and this may have implications for HIV-1 disease surveillance and treatment. The state of Maryland currently has the fourth highest AIDS case report rate in the United States. The goal of this study was to evaluate the prevalence of HIV-1 non-B subtypes in Maryland. The study population included individuals diagnosed with HIV in 2007 through the voluntary counseling and testing sites at the Maryland Department of Health and Mental Hygiene and HIV-infected patients who had genotyping performed at the University of Maryland Medical Center. Results:At the Department of Health and Mental Hygiene sites, 47 unique non-B subtype strains were identified representing a non-B prevalence of 12.9%. These non-B subtypes included CRF02_AG (n = 20), C (n = 11), A (n = 7), G (n = 5), D (n = 1), and unique recombinant forms (n = 3). The non-B patients were predominantly non-Hispanic black (95.7%) with 63.8% female. Although the majority of the HIV subtype B cases (65.3%) were identified from the Baltimore metropolitan area, most (80.9%) of the non-B cases were from the Maryland suburbs of Washington, DC. Among University of Maryland Medical Center patients, there were 30 non-B subtypes, representing a non-B prevalence of 1.9%. The non-B subtypes detected were CRF02_AG (n = 14), C (n = 6), A (n = 6), G (n = 2), D (n = 1), and unique recombinant forms (n = 1). Phylogenetic analysis of the non-B subtypes revealed that viral sequences from both sources were intermixed, confirming that both sampling frames were drawing from the same overall population. Conclusions:Multiple HIV-1 subtypes exist in the Baltimore-Washington metropolitan area with a significant non-B-infected population in the Maryland suburbs of Washington, DC, suggesting 2 independent epidemics of HIV in Maryland. Population-based surveillance inclusive of groups at higher risk of non-B strains is essential to monitor the prevalence and variations of HIV subtypes in Maryland and the United States.