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1.  Nelfinavir Inhibits Maturation and Export of Herpes Simplex Virus 1 
Journal of Virology  2014;88(10):5455-5461.
Nelfinavir (NFV) is an HIV-1 protease inhibitor with demonstrated antiviral activity against herpes simplex virus 1 (HSV-1) and several other herpesviruses. However, the stages of HSV-1 replication inhibited by NFV have not been explored. In this study, we investigated the effects of NFV on capsid assembly and envelopment. We confirmed the inhibitory effects of NFV on HSV-1 replication by plaque assay and found that treatment with NFV did not affect capsid assembly, activity of the HSV-1 maturational protease, or formation of DNA-containing capsids in the nucleus. Confocal and electron microscopy studies showed that these capsids were transported to the cytoplasm but failed to complete secondary envelopment and subsequent exit from the cell. Consistent with the microscopy results, a light-scattering band corresponding to enveloped virions was not evident following sucrose gradient rate-velocity separation of lysates from drug-treated cells. Evidence of a possibly related effect of NFV on viral glycoprotein maturation was also discovered. NFV also inhibited the replication of an HSV-1 thymidine kinase mutant resistant to nucleoside analogues such as acyclovir. Given that NFV is neither a nucleoside mimic nor a known inhibitor of nucleic acid synthesis, this was expected and suggests its potential as a coinhibitor or alternate antiviral therapeutic agent in cases of resistance.
IMPORTANCE Nelfinavir (NFV) is a clinically important antiviral drug that inhibits production of infectious HIV. It was reported to inhibit herpesviruses in cell culture. Herpes simplex virus 1 (HSV-1) infections are common and often associated with several diseases. The studies we describe here confirm and extend earlier findings by investigating how NFV interferes with HSV-1 replication. We show that early steps in virus formation (e.g., assembly of DNA-containing capsids in the nucleus and their movement into the cytoplasm) appear to be unaffected by NFV, whereas later steps (e.g., final envelopment in the cytoplasm and release of infectious virus from the cell) are severely restricted by the drug. Our findings provide the first insight into how NFV inhibits HSV-1 replication and suggest that this drug may have applications for studying the herpesvirus envelopment process. Additionally, NFV may have therapeutic value alone or in combination with other antivirals in treating herpesvirus infections.
PMCID: PMC4019105  PMID: 24574416
2.  Absence of posttransplantation lymphoproliferative disorder after allogeneic blood or marrow transplantation using posttransplantation cyclophosphamide as graft-versus-host disease prophylaxis 
Immunosuppressive regimens that effectively prevent graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT) have been associated with an increased incidence of posttransplantation lymphoproliferative disorder (PTLD) in the first year after transplantation. We evaluated the incidence of PTLD associated with the use of high-dose, posttransplantation cyclophosphamide (PTCy) as GVHD prophylaxis. From 2000-2011, 785 adult alloBMT patients received PTCy as GVHD prophylaxis at the Johns Hopkins Hospital, including 313 who received PTCy as sole GVHD prophylaxis. HLA-haploidentical or unrelated donor grafts were used for 526 (67%) patients. There were no cases of PTLD in the first year after alloBMT. PTLD is rare after alloBMT using PTCy, even in high-risk alternative donor transplants.
PMCID: PMC4051232  PMID: 23871780
3.  Blood and marrow transplant for lymphoma patients with HIV/AIDS 
Current opinion in oncology  2008;20(2):201-205.
Purpose of review
Important strides in the management of patients with HIV/AIDS-related lymphomas have been made in recent years. This review will discuss the role of bone marrow or peripheral stem-cell transplantation as a modality for patients with HIV and lymphoma.
Recent findings
In the era of highly active antiretroviral therapy, patients with HIV-associated lymphoma are generally being treated with standard or only slightly modified chemotherapy regimens. Autologous bone marrow and stem-cell transplant approaches in lymphoma patients have been successful. Case reports suggest that allogeneic transplantation for patients with HIV and hematologic malignancies merits further investigation.
High-dose hematopoietic stem-cell therapies with curative intent should be considered as standard therapeutic options in patients who otherwise are appropriate for such therapies.
PMCID: PMC4138614  PMID: 18300771
autologous bone marrow/stem-cell transplantation; HIV/AIDS; non-Hodgkin’s lymphoma
4.  EBV Related Lymphomas: New Approaches to Treatment 
PMCID: PMC3670765  PMID: 23549980
Epstein-Barr virus; Hodgkin lymphoma; Burkitt lymphoma; non-Hodgkin lymphoma; posttransplantation lymphoproliferative disorder; HIV-associated lymphomas; immunodeficiency; adoptive T-cell therapy; EBV-specific cytotoxic T-cells; rituximab; viral latency; EBV-DNA
5.  Outcomes of Related Donor HLA-Identical or HLA-Haploidentical Allogeneic Blood or Marrow Transplantation for Peripheral T Cell Lymphoma 
The role of allogeneic blood or marrow transplantation (alloBMT) for peripheral T cell lymphoma (PTCL) remains to be defined. There is growing interest in reduced-intensity conditioning (RIC) regimens and/or utilization of human leukocyte antigen haploidentical (haplo) grafts given concerns about treatment-associated toxicities and donor availability. We reviewed the outcomes of 44 consecutive, related donor alloBMTs for PTCL performed at Johns Hopkins Hospital from 1994 to 2011, including 18 RIC/haplo alloBMTs. Patients receiving RIC (n = 24) were older, with median age of 59 years (range, 24 to 70), than patients receiving myeloablative conditioning (MAC, n = 20), with median age of 46 years (range, 18 to 64), P =.01. The median age at RIC/haplo alloBMT was 60 years. The estimated 2-year progression-free survival (PFS) was 40% (95% confidence interval [CI], 26% to 55%) and overall survival (OS) was 43% (95% CI, 28% to 59%). In older patients (≥60, n = 14), the estimated 2-year PFS and OS were 38% (95% CI, 18% to 79%) and 45% (95% CI, 24% to 86%), respectively. On unadjusted analysis, there was a tendency toward superior outcomes for alloBMT in first remission versus beyond first remission, with an estimated 2-year PFS of 53% (95% CI, 33% to 77%) versus 29% (95% CI, 9% to 45%), P = .08. On competing risk analysis, the 1-year cumulative incidence of relapse was 38% for MAC/HLA-identical alloBMTs and 34% for RIC/haplo alloBMTs. Estimated 1-year nonrelapse mortality was 10% for MAC and 8% for RIC (11% for RIC/haplo alloBMT). On unadjusted landmark analysis, patients with acute grade II-IV or chronic graft-versus-host disease (GVHD) had a 17% probability of relapse (95% CI, 0% to 39%), compared with 66% (95% CI, 48% to 84%) in patients without GVHD, P = .04. Utilization of RIC and alternative donors expands treatment options in PTCL to those who are older and unable to tolerate high-dose conditioning, with outcomes comparable with approaches using myeloablative regimens and HLA-matched donors. AlloBMT may be appropriate in first remission in select high-risk cases.
PMCID: PMC4020434  PMID: 23370119
Peripheral T-cell lymphoma; Allogeneic blood or marrow; transplantation; Haploidentical; Reduced-intensity conditioning; Survival outcomes
6.  CpG Methylation as a Tool to Characterize Cell-Free Kaposi Sarcoma Herpesvirus DNA 
The Journal of Infectious Diseases  2012;205(7):1095-1099.
(See the editorial commentary by Stebbing and Bower, on pages 1032–4.)
We studied the presence of Kaposi sarcoma herpesvirus sequences in cell-free DNA (cfDNA) isolated from the blood of patients with AIDS-related Kaposi sarcoma (KS) and primary effusion lymphoma (PEL). The use of paramagnetic beads linked to methyl-CpG binding domain protein allowed separation of virion and cell-derived DNA. Only virion DNA was detected in the blood of KS patients, whereas cell-derived DNA was detected in a patient with AIDS-related PEL. The difference in the origins of cfDNA in these settings may in part reflect very different proliferative indices in KS and PEL tumor tissue.
PMCID: PMC3295606  PMID: 22357696
7.  Brief intensive therapy for older adults with newly diagnosed Burkitt or atypical Burkitt lymphoma/leukemia 
Leukemia & lymphoma  2012;54(3):483-490.
Older patients with Burkitt lymphoma/leukemia (BL) have inferior outcomes. Because cyclophosphamide is highly active in BL and can be dose-escalated without stem-cell rescue, we designed a short, cyclophosphamide-intensive regimen without anthracyclines for patients aged ≥30 with untreated, non-HIV-associated BL/atypical BL. Two cycles involving cyclophosphamide 1500 mg/m2, vincristine, rituximab, prednisone, methotrexate 3 g/m2, and intrathecal cytarabine were delivered 2 weeks apart, followed by intensification with high-dose cyclophosphamide (50 mg/kg/day for 4 days) and rituximab. Of 21 patients, median age 53 (range, 34–75), 71% had stage IV, 95% were high-risk and 29% had performance status 3–4. Response occurred in all evaluable patients post-cycle 2 and in 76% post-intensification. Five non-relapse deaths occurred (four before intensification). The estimated 1-year and 3-year event-free survival was 52%; 1-year and 3-year overall survival was 57%. Seventeen (81%) received intensification (median 30 days to intensification). Brief, anthracycline-sparing, intensive cyclophosphamide (BASIC) therapy yields durable remissions in poorer-risk BL/atypical BL.
PMCID: PMC4234101  PMID: 22835045
Atypical Burkitt lymphoma; Burkitt lymphoma; cyclophosphamide; unclassifiable B-cell lymphoma
8.  Randomized Trial of Paclitaxel versus Pegylated Liposomal Doxorubicin for Advanced Human Immunodeficiency Virus-associated Kaposi’s Sarcoma: Evidence for Symptom Palliation from Chemotherapy 
Cancer  2010;116(16):3969-3977.
Paclitaxel (PTX) and pegylated liposomal doxorubicin (PLD) are active cytotoxic agents for the treatment of human immunodeficiency (HIV) associated Kaposi’s sarcoma (KS). We performed a randomized trial comparing the efficacy and toxicity of PTX and PLD, and determine the effects of therapy on symptom palliation and quality of life.
Patients with advanced HIV-associated KS were randomly assigned to receive PTX (100 mg/m2) IV every 2 weeks, or PLD 20 mg/m2 IV every 3 weeks. The KS Functional Assessment of HIV (FAHI) Quality of Life instrument was used before and after every other treatment cycle.
The study included 73 analyzable patients enrolled between 1998 and 2002, including 36 in the PTX arm and 37 in the PLD arm; 73% received highly active antiretroviral therapy (HAART) and 32% had undetectable viral load (<400 copies/mL). Treatment was associated with significant improvement in pain (P=0.024) and swelling (P<0.001). Of the 36 patients who reported that pain interfered with their normal work or activities at baseline, 25 (69%) improved. Of the 41 patients who reported swelling at baseline, 38 (93%) improved. Comparing the PTX and PLD arms revealed comparable response rates (56% vs. 46%; p=0.49), median progression free survival (17.5 vs. 12.2 months; p=0.66), and 2-year survival (79% vs. 78%; p=0.75), but somewhat more grade 3–5 toxicity for PTX (84% vs. 66%, p=0.077).
Treatment with either PTX or PLD produces significant improvement in pain and swelling in patients with advanced, symptomatic, HIV-associated KS treated in the early HAART era.
PMCID: PMC3157242  PMID: 20564162
HIV infection; AIDS; Kaposi’s sarcoma; paclitaxel; pegylated liposomal doxorubicin
9.  Bortezomib salvage therapy in refractory acute adult T-cell leukemia/lymphoma 
Leukemia & lymphoma  2013;54(11):2563-2564.
PMCID: PMC4154876  PMID: 23445368
adult T-cell leukemia/lymphoma; bortezomib; HTLV-1
10.  Insights Into the Broad Cellular Effects of Nelfinavir and the HIV Protease Inhibitors Supporting Their Role in Cancer Treatment and Prevention 
Current opinion in oncology  2013;25(5):495-502.
Purpose of Review
The development of HIV protease inhibitors (PIs) more than two decades ago heralded a new era in HIV care, changing the infection from universally-fatal to chronic but controllable. With the widespread use of PIs, there was a reduction in the incidence and mortality of HIV-associated malignancies. Studies later found these drugs to have promising direct antitumor effects.
Recent findings
PIs have a wide range of effects on several cellular pathways that are important for tumorigenesis and independent of inhibition of the HIV protease, including reducing angiogenesis and cell invasion, inhibition of the Akt pathway, induction of autophagy, and promotion of apoptosis. Among PIs, Nelfinavir appears to have the most potent and broad antineoplastic activities, and also affects replication of the oncogenic herpesviruses Kaposi sarcoma-associated herpesvirus and Epstein-Barr virus. Nelfinavir is being studied for the prevention and treatment of a wide range of malignancies in persons with and without HIV infection.
Nelfinavir and other PIs are safe, oral drugs that have promising antitumor properties, and may prove to play an important role in the prevention and treatment of several cancers. Additional insights into PIs’ mechanisms of action may lead to the development of novel cancer chemotherapy agents.
PMCID: PMC4029099  PMID: 23872785
HIV protease inhibitor; nelfinavir; cancer; Kaposi sarcoma; treatment
12.  Molecular and Clinical Assessment in the Treatment of AIDS Kaposi’s Sarcoma with Valproic Acid 
The AIDS Malignancy Consortium (AMC) undertook a pilot trial of valproic acid (VA) in patients with AIDS-associated Kaposi’s sarcoma (KS). Treatment was associated with low toxicity, but the KS clinical response and KS herpesvirus lytic induction rates were not sufficiently high to meet pre-defined criteria for efficacy.
PMCID: PMC2952388  PMID: 19911999
Valproic acid; AIDS; HIV; KSHV; HHV-8; Kaposi sarcoma
13.  Effects of Chemotherapy in AIDS-Associated Non-Hodgkin's Lymphoma on Kaposi's Sarcoma Herpesvirus DNA in Blood 
Journal of Clinical Oncology  2009;27(15):2496-2502.
To determine the relative frequency with which Kaposi's sarcoma–associated herpesvirus/HHV-8 (KSHV) DNA is detected in peripheral-blood mononuclear cells (PBMCs) and in plasma of patients with AIDS-KS and AIDS-associated non-Hodgkin's lymphoma (NHL; AIDS-NHL); to determine whether the presence of viral DNA in plasma reflects lysis of tumor cells or reflects the presence of viremia (ie, virion-encapsidated DNA); and to determine the effect of lymphoma therapy on KSHV DNA.
Patients and Methods
Samples were obtained from patients enrolled in AIDS Malignancy Consortium clinical trials and from healthy donors. Real time PCR was used to quantify KSHV DNA in peripheral blood mononuclear cells (PBMC) and plasma. DNase digestion and fragment size determination studies were used to characterize the DNA detected.
In patients with AIDS-KS, KSHV DNA was detected in PBMC (54%) and in plasma (62%). In patients with AIDS-NHL, KSHV DNA was detected in PBMC (19%) and in plasma (22%). Median copy numbers also differed. KSHV DNA in plasma appeared to be encapsidated. In six patients with AIDS-NHL who were treated with chemotherapy (with or without rituximab), KSHV copy number declined in PBMC and in plasma.
KSHV DNA is sometimes detected in PBMC or in plasma of patients with AIDS-NHL without KS. Among patients with KSHV DNA detected in PBMC or in plasma, copy number does not distinguish between patients with AIDS-NHL and AIDS-KS. KSHV DNA in plasma likely reflects viremia and not simply lysis of tumor or other KSHV-infected cells. KSHV DNA copy number in PBMC and in plasma declined with lymphoma-directed cytotoxic chemotherapy in each of the six patients studied.
PMCID: PMC2684854  PMID: 19349542
14.  Phase II Study of Risk-Adapted Therapy of Newly Diagnosed, Aggressive Non-Hodgkin Lymphoma Based on Midtreatment FDG-PET Scanning 
In newly diagnosed aggressive non-Hodgkin lymphoma (NHL), a positive midtreatment fluorine-18 fluorodeoxyglucose positron emission tomography (PET) scan often carries a poor prognosis, with reported 2-year event-free survival (EFS) rates of 0% to 30% after standard therapy. To determine the outcome of early treatment intensification for midtreatment PET-positive disease, a phase II trial of risk-adapted therapy was conducted. Fifty-nine newly diagnosed patients, 98% with B cell lymphoma, had PET/CT performed after 2 or 3 cycles of first-line chemotherapy. Those with negative PET on semiquantitative visual interpretation completed standard therapy. Those with positive PET received platinum-based salvage chemotherapy, high-dose therapy, and autologous stem cell transplantation (ASCT). Midtreatment PET was positive in 33 (56%); 28 received ASCT with an actuarial 2-year EFS of 75% (95% confidence interval, 60%–93%). On intention-to-treat analysis, 2-year EFS was 67% (53%–86%) in all PET-positive patients and 89% (77%–100%) in PET-negative patients. No association was found between the International Prognostic Index category and the midtreatment PET result. The favorable outcome achieved here in historically poor-risk patients warrants further, more definitive investigation of treatment modification based on early PET scanning.
PMCID: PMC4020440  PMID: 19167684
Lymphoma; Positron emission tomography (PET); Prognosis; Autologous stem cell transplantation
15.  Cytokine signaling pathway polymorphisms and AIDS-related non-Hodgkin lymphoma risk in the Multicenter AIDS Cohort Study 
AIDS (London, England)  2010;24(7):1025-1033.
Cytokine stimulation of B-cell proliferation may be an important etiologic mechanism for acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). The Epstein-Barr virus may be a co-factor, particularly for primary central nervous system (CNS) tumors, which are uniformly EBV-positive in the setting of AIDS. Thus, we examined associations of genetic variation in IL10 and related cytokine signaling molecules (IL10RA, CXCL12, IL13, IL4, IL4R, CCL5 and BCL6) with AIDS-related NHL risk and evaluated differences between primary CNS and systemic tumors. We compared 160 Multicenter AIDS Cohort Study (MACS) participants with incident lymphomas, of which 90 followed another AIDS diagnosis, to HIV-1-seropositive controls matched on duration of lymphoma-free survival post-HIV-1 infection (N=160) or post-AIDS diagnosis (N=90). We fit conditional logistic regression models to estimate odds ratios (ORs) and 95 percent confidence intervals (95%CIs). Carriage of at least one copy of the T allele for the IL10 rs1800871 (as compared to no copies) was associated with decreased AIDS-NHL risk specific to lymphomas arising from the CNS (CC vs. CT/TT: OR=0.3; 95%CI: 0.1, 0.7) but not systemically (CC vs. CT/TT: OR=1.0; 95%CI: 0.5, 1.9) (Pheterogeneity=0.03). Carriage of two copies of the “low IL10” haplotype rs1800896_A/rs1800871_T/rs1800872_A was associated with decreased lymphoma risk that varied by number of copies (Ptrend=0.02). None of the ORs for the other studied polymorphisms was significantly different from 1.0. Excessive IL10 response to HIV-1 infection may be associated with increased risk of NHL, particularly in the CNS. IL10 dysregulation may be an important etiologic pathway for EBV-related lymphomagenesis.
PMCID: PMC3950937  PMID: 20299965
cytokine; SNPs; AIDS-related lymphoma
16.  Serum levels of the chemokine CXCL13, genetic variation in CXCL13 and its receptor CXCR5, and HIV-associated non-Hodgkin B cell lymphoma risk 
CXCL13 and CXCR5 are a chemokine and receptor pair whose interaction is critical for naïve B cell trafficking and activation within germinal centers. We sought to determine whether CXCL13 levels are elevated prior to HIV-associated non-Hodgkin B-cell lymphoma (AIDS-NHL), and whether polymorphisms in CXCL13 or CXCR5 are associated with AIDS-NHL risk and CXCL13 levels in a large cohort of HIV-infected men.
CXCL13 levels were measured in sera from 179 AIDS-NHL cases and 179 controls at three time-points. TagSNPs in CXCL13 (n=16) and CXCR5 (n=11) were genotyped in 183 AIDS-NHL cases and 533 controls. Odds ratios (OR) and 95% confidence intervals (CIs) for the associations between one unit increase in log CXCL13 levels and AIDS-NHL, as well as tagSNP genotypes and AIDS-NHL, were computed using logistic regression. Mixed linear regression was used to estimate mean ratios (MR) for the association between tagSNPs and CXCL13 levels.
CXCL13 levels were elevated >3 years (OR=3.24, 95% CI=1.90–5.54), 1–3 years (OR=3.39, 95% CI=1.94–5.94) and 0–1 year (OR=3.94, 95% CI=1.98–7.81) prior to an AIDS-NHL diagnosis. The minor allele of CXCL13 rs355689 was associated with reduced AIDS-NHL risk (ORTCvsTT=0.65; 95% CI=0.45–0.96) and reduced CXCL13 levels (MRCCvsTT=0.82, 95% CI=0.68–0.99). The minor allele of CXCR5 rs630923 was associated with increased CXCL13 levels (MRAAvsTT=2.40, 95% CI=1.43–4.50).
CXCL13 levels were elevated preceding an AIDS-NHL diagnosis, genetic variation in CXCL13 may contribute to AIDS-NHL risk, and CXCL13 levels may be associated with genetic variation in CXCL13 and CXCR5.
CXCL13 may serve as a biomarker for early AIDS-NHL detection.
PMCID: PMC3703445  PMID: 23250934
Non-Hodgkin Lymphoma; HIV; CXCL13; CXCR5; chemokine
17.  HIV-1 DNA Is Detected in Bone Marrow Populations Containing CD4+ T Cells but Is not Found in Purified CD34+ Hematopoietic Progenitor Cells in Most Patients on Antiretroviral Therapy 
The Journal of Infectious Diseases  2012;205(6):1014-1018.
Identifying cellular reservoirs of human immunodeficiency virus type 1 (HIV-1) in patients on antiretroviral therapy (ART) is critical to finding a cure for HIV-1. In addition to resting CD4+ T cells, CD34+ hematopoietic progenitor cells have been proposed as another reservoir. We obtained bone marrow aspirates from 11 patients on ART who had undetectable plasma HIV-1 RNA. HIV-1 DNA was detected in CD4+ T cells from peripheral blood in all patients and from bone marrow cellular fractions containing T cells in most patients. We did not find HIV-1 DNA in highly purified CD34+ populations using either a sensitive real-time polymerase chain reaction assay or a coculture assay for replication-competent HIV-1.
PMCID: PMC3282572  PMID: 22275402
18.  Comparison of Humoral Immune Responses to Epstein-Barr Virus and Kaposi’s Sarcoma–Associated Herpesvirus Using a Viral Proteome Microarray 
The Journal of Infectious Diseases  2011;204(11):1683-1691.
Background. Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, and Kaposi’s sarcoma–associated herpesvirus (KSHV) has a restricted seroprevalence. Both viruses are associated with malignancies that have an increased frequency in individuals who are coinfected with human immunodeficiency virus type 1 (HIV-1).
Methods. To obtain an overview of humoral immune responses to these viruses, we generated a protein array that displayed 174 EBV and KSHV polypeptides purified from yeast. Antibody responses to EBV and KSHV were examined in plasma from healthy volunteers and patients with B cell lymphoma or with AIDS-related Kaposi’s sarcoma or lymphoma.
Results. In addition to the commonly studied antigens, IgG responses were frequently detected to the tegument proteins KSHV ORF38 and EBV BBRF and BGLF2 and BNRF1 and to the EBV early lytic proteins BRRF1 and BORF2. The EBV vIL-10 protein was particularly well recognized by plasma IgA. The most intense IgG responses to EBV antigens occurred in HIV-1–positive patients. No clear correlation was observed between viral DNA load in plasma and antibody profile.
Conclusions. The protein array provided a sensitive platform for global screening; identified new, frequently recognized viral antigens; and revealed a broader humoral response to EBV compared with KSHV in the same patients.
PMCID: PMC3203236  PMID: 21990424
19.  A Protein Array Screen for Kaposi's Sarcoma-Associated Herpesvirus LANA Interactors Links LANA to TIP60, PP2A Activity, and Telomere Shortening 
Journal of Virology  2012;86(9):5179-5191.
The Kaposi's sarcoma-associated herpesvirus (KSHV) LANA protein functions in latently infected cells as an essential participant in KSHV genome replication and as a driver of dysregulated cell growth. To identify novel LANA protein-cell protein interactions that could contribute to these activities, we performed a proteomic screen in which purified, adenovirus-expressed Flag-LANA protein was incubated with an array displaying 4,192 nonredundant human proteins. Sixty-one interacting cell proteins were consistently detected. LANA interactions with high-mobility group AT-hook 1 (HMGA1), HMGB1, telomeric repeat binding factor 1 (TRF1), xeroderma pigmentosum complementation group A (XPA), pygopus homolog 2 (PYGO2), protein phosphatase 2A (PP2A)B subunit, Tat-interactive protein 60 (TIP60), replication protein A1 (RPA1), and RPA2 proteins were confirmed in coimmunoprecipitation assays. LANA-associated TIP60 retained acetyltransferase activity and, unlike human papillomavirus E6 and HIV-1 TAT proteins, LANA did not reduce TIP60 stability. The LANA-bound PP2A B subunit was associated with the PP2A A subunit but not the catalytic C subunit, suggesting a disruption of PP2A phosphatase activity. This is reminiscent of the role of simian virus 40 (SV40) small t antigen. Chromatin immunoprecipitation (ChIP) assays showed binding of RPA1 and RPA2 to the KSHV terminal repeats. Interestingly, LANA expression ablated RPA1 and RPA2 binding to the cell telomeric repeats. In U2OS cells that rely on the alternative mechanism for telomere maintenance, LANA expression had minimal effect on telomere length. However, LANA expression in telomerase immortalized endothelial cells resulted in telomere shortening. In KSHV-infected cells, telomere shortening may be one more mechanism by which LANA contributes to the development of malignancy.
PMCID: PMC3347335  PMID: 22379092
20.  Conserved Herpesvirus Kinases Target the DNA Damage Response Pathway and TIP60 Histone Acetyltransferase to Promote Virus Replication 
Cell host & microbe  2011;10(4):390-400.
Herpesviruses, which are major human pathogens, establish life-long persistent infections. Although the α-, β-, and γ-herpesviruses infect different tissues and cause distinct diseases, they each encode a conserved serine/threonine kinase critical for virus replication and spread. The extent of substrate conservation and the key common cell signalling pathways targeted by these kinases are unknown. Using a human protein microarray high-throughput approach we identify shared substrates of the conserved kinases from herpes simplex virus, human cytomegalovirus, Epstein-Barr virus (EBV) and Kaposi's sarcoma associated herpesvirus. DNA damage response (DDR) proteins were statistically enriched and the histone acetyltransferase TIP60, an upstream regulator of the DDR pathway, was required for efficient herpesvirus replication. During EBV replication, TIP60 activation by the BGLF4 kinase triggers EBV-induced DDR and also mediates induction of viral lytic gene expression. Identification of key cellular targets of the conserved herpesvirus kinases will facilitate the development of broadly effective anti-viral strategies.
PMCID: PMC3253558  PMID: 22018239
21.  Use of antineoplastic agents in cancer patients with HIV/AIDS 
The Lancet Oncology  2011;12(9):905-912.
In the era of highly active antiretroviral therapy (HAART), patients with human immunodeficiency virus (HIV) have reduced morbidity and mortality of AIDS-related complications. However, there is an increase in the prevalence of AIDS-defining and non-AIDS-defining cancers. This article provides an up-to-date review of management of HAART pharmacotherapy in the context of cytotoxic chemotherapy or targeted antineoplastic agents.
PMCID: PMC3343721  PMID: 21570912
antiretroviral; antineoplastic agents; pharmacology
22.  Sustained Elite Suppression of Replication Competent HIV-1 in a Patient Treated With Rituximab Based Chemotherapy 
The mechanism of elite control of HIV-1 replication is not fully understood. While immunosuppression due to rituximab based chemotherapy has been associated with increased replication of HBV, CMV, and HIV-1, control of replication-competent HIV-1 was maintained in an elite controller/suppressor treated with a regimen that included vincristine, cyclophosphamide, prednisone, four rounds of plasmapheresis and ten cycles of rituximab. The data suggests that de-novo antibody responses do not play a significant role in the control of viral replication in these patients.
PMCID: PMC3117974  PMID: 21550842
23.  B cell-stimulatory cytokines and markers of immune activation are elevated several years prior to the diagnosis of systemic AIDS-associated non-Hodgkin B cell lymphoma 
The risk of developing non-Hodgkin lymphoma (NHL) is greatly increased in HIV infection. The aim of this study was to determine if elevated serum levels of molecules associated with B cell activation precede the diagnosis of AIDS-associated NHL.
Serum levels of B cell activation-associated molecules, interleukin-6 (IL6), interleukin-10 (IL10), soluble CD23 (sCD23), soluble CD27 (sCD27), soluble CD30 (sCD30), C-reactive protein (CRP), and IgE were determined in 179 NHL cases and HIV+ controls in the Multicenter AIDS Cohort Study, collected at up to three time points per subject, 0–5 years prior to AIDS-NHL diagnosis.
Serum IL6, IL10, CRP, sCD23, sCD27, and sCD30 levels were all significantly elevated in the AIDS-NHL group, when compared to HIV+ controls or to AIDS controls, after adjusting for CD4 T cell number. Elevated serum levels of B cell activation-associated molecules were seen to be associated with the development of systemic (non-CNS) NHL, but not with the development of primary CNS lymphoma.
Levels of certain B cell stimulatory cytokines and molecules associated with immune activation are elevated for several years preceding the diagnosis of systemic AIDS-NHL. This observation is consistent with the hypothesis that chronic B cell activation contributes to the development of these hematologic malignancies.
Marked differences in serum levels of several molecules are seen for several years pre-diagnosis in those who eventually develop AIDS-NHL. Some of these molecules may serve as candidate biomarkers and provide valuable information to better define the etiology of NHL.
PMCID: PMC3132317  PMID: 21527584
lymphoma; B cell; cytokines; AIDS; immune activation
24.  Imaging Virus-Associated Cancer 
Current Pharmaceutical Design  2008;14(28):3048-3065.
Cancer remains an important and growing health problem. Researchers have made great progress in defining genetic and molecular alterations that contribute to cancer formation and progression. Molecular imaging can identify appropriate patients for targeted cancer therapy and may detect early biochemical changes in tumors during therapy, some of which may have important prognostic implications. Progress in this field continues largely due to a union between molecular genetics and advanced imaging technology. This review details uses of molecular-genetic imaging in the context of tumor-associated viruses. Under certain conditions, and particularly during pharmacologic stimulation, gammaherpesviruses will express genes that enable imaging and therapy in vivo. The techniques discussed are readily translatable to the clinic.
PMCID: PMC3369625  PMID: 18991718
EBV; molecular imaging; FIAU; bortezomib; thymidine kinase

Results 1-25 (52)