- Letter to the Editor
- Open Access
HIV Co-receptor usage in HIV-related non-hodgkin's lymphoma
© Reid and Morris; licensee BioMed Central Ltd. 2012
- Received: 5 January 2012
- Accepted: 15 March 2012
- Published: 15 March 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).
- Non-hodgkins lymphoma
- Co-receptor usage
- CCR5 CXCR4
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.
HIV Co-receptor Tropism and SDF1 3'A among Individuals with Non-Hodgkin's Lymphoma
Age median (range)
Median CD4 Count (range)
Median log10 Viral Load (range)
HIV co-receptor tropism (%)
Dual Mixed (CCR5 and CXCR4)
SDF1 polymorphism1 (%)
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.
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.
- 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.PubMedView ArticleGoogle Scholar
- Bonnet F, Chene G: Evolving epidemiology of malignancies in HIV. Curr Opin Oncol. 2008, 20: 534-540. 10.1097/CCO.0b013e32830a5080.PubMedView ArticleGoogle Scholar
- 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.PubMedView ArticleGoogle Scholar
- 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.PubMedView ArticleGoogle Scholar
- 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.PubMedView ArticleGoogle Scholar
- 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.PubMedPubMed CentralView ArticleGoogle Scholar
- 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.PubMedView ArticleGoogle Scholar
- 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.PubMedView ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.PubMedView ArticleGoogle Scholar
- 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.PubMedView ArticleGoogle Scholar
- 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.PubMedGoogle Scholar
- 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.PubMedView ArticleGoogle Scholar
- 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.PubMedGoogle Scholar
- 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.PubMedView ArticleGoogle Scholar
- 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.PubMedView ArticleGoogle Scholar
- 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.PubMedView ArticleGoogle Scholar
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