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HIV Co-receptor usage in HIV-related non-hodgkin's lymphoma
Infectious Agents and Cancer volume 7, Article number: 6 (2012)
In this study 15 banked samples of HIV-related Non-Hodgkin's Lymphoma (NHL) cases were tested for HIV co-receptor usage and SDF1 3'A polymorphism. Reportable tropism from 9 plasma samples had 1 (11.1%) HIV case with CXCR4 and 8 (88.9%) with CCR5 usage, even though most of the cases occurred at a late stage of HIV (2/3 had CD4 counts below 200), where expected CXCR4 usage would be 60%. Based on the expected proportion of less than 50% CCR5 in chronically infected individuals, this would suggest that in NHL may be associated with CCR5 usage (P = 0.04).
Highly active antiretroviral treatment (HAART) has prolonged survival in HIV infected individuals , however, HIV associated malignancies remain relatively common . Lymphoma is a frequent HIV-related malignancy , that generally presents in late HIV disease, possibly related to worsening immune function that allows latent Epstein Barr Virus (EBV) in memory B cells to generate a proliferative condition [4, 5]. We considered what HIV factors may also play a role in lymphoma and noted that with later HIV disease stages the virus acquires CXCR4 co-receptor usage . In early stage HIV infection, at most, only about 15% are dual/mixed (DM) tropic for CCR5 and CXCR4 [7, 8], then in late disease stages, DM tropism or pure CXCR4 tropism reaches up to 60% when measured by the enhanced tropism assay , and is the highest with CD4 ≤ 200 cells/ml [10, 11]. The chemokine receptor CXCR4 is also highly expressed in hematological malignancies [12, 13]. The chemokine for CXCR4, stromal cell derived factor 1 (SDF1), has also been associated with HIV associated Non-Hodgkin's lymphoma (NHL) when individuals have a polymorphism in the SDF1 gene from G to A transition at position 801 (SDF1-3'A) that increased with homozygosity . In North America, SDF1-3'A is expected in 21% of Caucasians . Although there was some suggestion that SDF1-3'A is associated with HIV disease progression , and CXCR4 tropic virus . Based on these observations, we examined whether HIV co-receptor usage and the SDF1 polymorphisms were associated with HIV-related NHL.
A study protocol was submitted and approved to the AIDS and Cancer Specimen Resource (ACSR) to supply 16 samples of NHL from HIV-infected individuals that had plasma and PBMC samples at a time of viral load greater than 1000, the threshold required for the Trofile assay (Monogram Biosciences Inc.). An IRB approval was obtained to collect and test these samples with diagnosis, demographics, HIV viral load, CD4 count for each subject. Samples were shipped from two ACSR repositories on dry ice and were processed for plasma to be sent for Trofile ES assay. The PBMCs were processed at the UCSD Center for AIDS Research Genomics Core laboratory. SDF1 polymorphisms were done with SNP analysis for the SDF 1-3'A polymorphism (Applied Biosystems). Data analysis employed SAS v 9.2 statistical software to describe the frequencies of HIV co-receptor tropism, SDF1-3'A, demographics, CD4 counts and HIV viral loads at time of the samples. Rates of expected proportions were compared with in a one-sample binomial proportion test for statistical significance in SAS v9.2.
There were 15 paired samples from HIV-infected individuals with confirmed NHL according to the ACSR database. Cases of HIV-related NHL were mainly male (93%) with median age of 47 (Table 1) and CD4 count ≤ 200 cells/ml in 9 (60%) cases. The median CD4 count was 148 (range 5-1056) and the median log10 viral load was 4.54 log copies/ml (range 3.32-5.88). Trofile assays were performed on all samples but 6 of the samples failed to culture and were non-reportable. Only one reportable tropism had DM tropism (11.1%, 95% Exact confidence interval 0.3-48.2%) and eight were CCR5 (88.9%, 95% Exact confidence interval (CI) 68.3-100%). Based on an expected estimate of 50% CCR5 use in late stage HIV-infected individuals the proportion of CCR5 tropism in the NHL samples was higher that expected ((P = 0.04). Tropism reportable cases had CD4 counts with median of 148 cells/ml (range 5-821). Those with reportable tropism did not differ in CD4 and viral load to those without a reportable tropism (Wilcoxon two sample t approximation p = 0.39 and p = 0.95). All PBMC samples were testing for the SDF polymorphism and four were heterozygous for the SDF1-3'A allele (26.7%, 95% CI 7.8-55.1). This rate of SDF1-3'A was no greater than expected in the general population based on one sided binomial proportion test against a base proportion of 21% (P = 0.39). Of the samples that had reportable tropism there were three (33.3%) with SDF-3'A heterozygosity. The one DM tropism was a SDF-3'A heterozygote compared to 25% of CCR5 tropism.
This is the first data that described the viral co-receptor tropism in HIV-infected subjects with NHL. The finding of only one of nine subjects had CXCR4 co-receptor usage using the most sensitive assay was lower than would have been expected and suggests a preponderance of CCR5 use in the NHL subjects. In our cases, SDF1-3'A was not significantly higher than the expected population levels. Although SD1-3'A was found with the only CXCR4 tropism, there was not enough outcomes to verify an association. Contrary to our initial hypothesis, our finding suggests, if there exists a relationship of NHL with HIV co-receptor, it will be with persistent CCR5 usage, but further studies are needed to validate this association.
Lima VD, Hogg RS, Harrigan PR, Moore D, Yip B, Wood E, et al: Continued improvement in survival among HIV-infected individuals with newer forms of highly active antiretroviral therapy. AIDS. 2007, 21: 685-692. 10.1097/QAD.0b013e32802ef30c.
Bonnet F, Chene G: Evolving epidemiology of malignancies in HIV. Curr Opin Oncol. 2008, 20: 534-540. 10.1097/CCO.0b013e32830a5080.
Engels EA, Pfeiffer RM, Goedert JJ, Virgo P, McNeel TS, Scoppa SM, et al: Trends in cancer risk among people with AIDS in the United States 1980-2002. AIDS. 2006, 20: 1645-1654. 10.1097/01.aids.0000238411.75324.59.
Pietersma F, Piriou E, van Baarle D: Immune surveillance of EBV-infected B cells and the development of non-Hodgkin lymphomas in immunocompromised patients. Leuk Lymphoma. 2008, 49: 1028-1041. 10.1080/10428190801911662.
Suarez F, Lortholary O, Hermine O, Lecuit M: Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood. 2006, 107: 3034-3044. 10.1182/blood-2005-09-3679.
Shepherd JC, Jacobson LP, Qiao W, Jamieson BD, Phair JP, Piazza P, et al: Emergence and persistence of CXCR4-tropic HIV-1 in a population of men from the multicenter AIDS cohort study. J Infect Dis. 2008, 198: 1104-1112. 10.1086/591623.
de Mendoza C, Rodriguez C, Garcia F, Eiros JM, Ruiz L, Caballero E, et al: Prevalence of X4 tropic viruses in patients recently infected with HIV-1 and lack of association with transmission of drug resistance. J Antimicrob Chemother. 2007, 59: 698-704. 10.1093/jac/dkm012.
Frange P, Galimand J, Goujard C, Deveau C, Ghosn J, Rouzioux C, et al: High frequency of X4/DM-tropic viruses in PBMC samples from patients with primary HIV-1 subtype-B infection in 1996-2007: the French ANRS CO06 PRIMO Cohort Study. J Antimicrob Chemother. 2009, 64: 135-141. 10.1093/jac/dkp151.
Wilkin TJ, Goetz MB, Leduc R, Skowron G, Su Z, Chan ES, et al: Reanalysis of coreceptor tropism in HIV-1-infected adults using a phenotypic assay with enhanced sensitivity. Clin Infec Dis: an official publication of the Infectious Diseases Society of America. 2011, 52: 925-928. 10.1093/cid/cir072.
Brumme ZL, Goodrich J, Mayer HB, Brumme CJ, Henrick BM, Wynhoven B, et al: Molecular and clinical epidemiology of CXCR4-using HIV-1 in a large population of antiretroviral-naive individuals. J Infect Dis. 2005, 192: 466-474. 10.1086/431519.
Hunt PW, Harrigan PR, Huang W, Bates M, Williamson DW, McCune JM, et al: Prevalence of CXCR4 tropism among antiretroviral-treated HIV-1-infected patients with detectable viremia. J Infect Dis. 2006, 194: 926-930. 10.1086/507312.
Zeng DF, Kong PY, Chen XH, Wei L, Chang C, Peng XG: The expression and clinical significance of stromal cell-derived factor-1 and CXCR4 in acute leukemia and malignant lymphoma. Zhonghua Nei Ke Za Zhi. 2005, 44: 522-524.
Piovan E, Tosello V, Indraccolo S, Cabrelle A, Baesso I, Trentin L, et al: Chemokine receptor expression in EBV-associated lymphoproliferation in hu/SCID mice: implications for CXCL12/CXCR4 axis in lymphoma generation. Blood. 2005, 105: 931-939.
Rabkin CS, Yang Q, Goedert JJ, Nguyen G, Mitsuya H, Sei S: Chemokine and chemokine receptor gene variants and risk of non-Hodgkin's lymphoma in human immunodeficiency virus-1-infected individuals. Blood. 1999, 93: 1838-1842.
Winkler C, Modi W, Smith MW, Nelson GW, Wu X, Carrington M, et al: Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC). Science. 1998, 279: 389-393. 10.1126/science.279.5349.389.
Ioannidis JP, Rosenberg PS, Goedert JJ, Ashton LJ, Benfield TL, Buchbinder SP, et al: Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data. Ann Intern Med. 2001, 135: 782-795.
Daar ES, Lynn HS, Donfield SM, Lail A, O'Brien SJ, Huang W, et al: Stromal cell-derived factor-1 genotype, coreceptor tropism, and HIV type 1 disease progression. J Infect Dis. 2005, 192: 1597-1605. 10.1086/496893.
his work was performed with the support of the UCSD Center for AIDS Research (NIAID 5 P30 AI36214) and Moores UCSD Cancer Center (NCI 5P30 CA23100). Other support includes NIAID P01 AI74621 and NIDA P50 DA26306.
The authors declare that they have no competing interests.
Both authors (ER and SM) contributed substantively to the design, acquisition of data, and drafting of the manuscript. ER arranged for the samples to be available. SM oversaw the sample processing and testing. SM did the analysis and was the primary authorship of the paper. All authors read and approved the final manuscript.
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Reid, E., Morris, S.R. HIV Co-receptor usage in HIV-related non-hodgkin's lymphoma. Infect Agents Cancer 7, 6 (2012). https://doi.org/10.1186/1750-9378-7-6
- Non-hodgkins lymphoma
- Co-receptor usage
- CCR5 CXCR4