Resistance to HIV‐1 infection among African sex workers is associated with global hyporesponsiveness in interleukin4 production

Trivedi, Harsha N.; Plummer, Francis A.; Anzala, Aggrey O.; Njagi, Ephantus; Bwayo, Job J.; Ngugi, Elizabeth; Embreé, Joanne; HayGlass, Kent T.

doi:10.1096/fj.00-0619fje

Cited by 12 publications

(9 citation statements)

References 56 publications

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“…Instead, the protective phenotype is associated with adaptive cellular and mucosal responses to HIV, reduced systemic immune activation, and an elevated frequency of regulatory T cells compared to HIV-uninfected controls (1,2,12,(23)(24)(25)50). These HESN women have elevated expression of HIV inhibitory factors at the genital tract, including serpins, other antiproteases, SLPI, and RANTES, as well as several undefined factors (11,21,22,50). In addition, endogenous antiretroviral elements, such as APOBECs and TRIM-5␣, may also be important in resistance to HIV infection.…”

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confidence: 99%

A Genetic Polymorphism of FREM1 Is Associated with Resistance against HIV Infection in the Pumwani Sex Worker Cohort

Luo

Sainsbury

Tuff

et al. 2012

J Virol

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A subgroup of women enrolled in the Pumwani sex worker cohort remain seronegative and PCR negative for human immunodeficiency virus type 1 despite repeated exposure through high-risk sex work. Studies have shown that polymorphisms of genes involved in antigen presentation and viral restriction factors are associated with resistance to HIV infection. To discover other possible genetic factors underlying this HIV-resistant phenotype, we conducted an exploratory nonbiased, low-resolution, genome-wide single-nucleotide polymorphism (SNP) analysis comparing 60 HIV-resistant women to 48 HIV-infected controls. The SNP minor allele rs1552896, in an intron of FREM1, was significantly associated with the resistant phenotype (P ‫؍‬ 1.68 ؋ 10 ؊5 ; adjusted P ‫؍‬ 2.37 ؋ 10 ؊4 ; odds ratio [OR], 9.51; 95% confidence interval [CI], 2.82 to 32.05). We expanded the sample size by genotyping rs1552896 in the Pumwani cohort and comparing 114 HIV-resistant women to 609 HIV-infected controls and confirmed the association (P ‫؍‬ 1.7 ؋ 10 ؊4 ; OR, 2.67; 95% CI, 1.47 to 4.84). To validate the association in a second cohort, we genotyped 783 women enrolled in a mother-child health study and observed the minor allele of rs1552896 enriched in HIV-uninfected women (n ‫؍‬ 488) compared to HIV-infected enrollees (n ‫؍‬ 295) (P ‫؍‬ 0.036; OR, 1.69; 95% CI, 0.98 to 2.93). Quantitative reverse transcription-PCR showed that FREM1 mRNA was highly expressed in tissues relevant for HIV-1 infection, and immunohistochemical analysis revealed that FREM1 protein is expressed in the ectocervical mucosa of HIV-resistant women. The significant association of rs1552896 with an HIV-resistant phenotype, together with the expression profile of FREM1 in tissues relevant to HIV infection, suggests that FREM1 is a potentially novel candidate gene for resistance to HIV infection.

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confidence: 99%

A Genetic Polymorphism of FREM1 Is Associated with Resistance against HIV Infection in the Pumwani Sex Worker Cohort

Luo

Sainsbury

Tuff

et al. 2012

J Virol

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“…The findings by Trivedi et al [8] that a subgroup of the Kenyan APSWs that are resistant to HIV-1 infection are hypo-producers of IL-4 provided the reason for their resistance to HIV-1 infection. The low level of IL-4 production may suggest that these women may have an early stop codon mutation in the gene that inhibits the synthesis of both IL-4 and IL-4 delta 2 splice variant.…”

Section: Hypothesis: Over-production Of Il-4 Delta 2 May Cause Hiv-1 mentioning

confidence: 98%

“…Trivedi et al [8] studied the levels of Thl and Th2 cytokines in the serum of the HIV-1 resistant APSWs in Kenya. It was reported that they exhibited enhanced level of Interferon gamma but a very low level of the Th2 cytokine IL-4.…”

Section: Studies On Hiv-1 Resistant Apsws In Africamentioning

confidence: 99%

“…All 6 women did not carry the CCR5 (delta) 32 mutation and most probably had increased CCL3L1 gene copy number. A recent study [8] reported that the seronegative APSWs hypo-expressed IL-4. The present review presents a hypothesis that the highly HIV-1 resistant sex workers that were multiply infected by HIV-1 and did not respond with antiviral cytotoxic cells, may be producers of large amounts of IL-4 delta 2, the natural antagonist of Interleukin-4.…”

Section: Introductionmentioning

confidence: 97%

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The Molecular Mechanism of Human Resistance to HIV-1 Infectionin Persistently Infected Individuals—A Review, Hypothesis and Implications

Becker

2005

Virus Genes

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Resistance to HIV-1 infection in Europeans is associated with a mutation in the gene that codes for the CCR5 protein that is present in Th2 cells and serves as a coreceptor for HIV-1 R5 strain. A deletion of 32 amino acids from the cytokine receptor prevents infection. This mutation prevails in Europeans and is absent in Africans. However, duplication of a gene that codes for a chemokine that binds to the CCR5 was discovered in Africans (mean gene copy 6 while in non-Africans the mean gene copy is 3). Higher expression of these genes protects T cells against HIV-1 infection in vitro. It should be noted that resistance to HIV-1 R5 variant does not protect against HIV-1 R4 variant. It was reported that a minority of highly HIV-1 exposed African professional sex workers (APSW) were resistant to the virus infection during a 10 years period. Recently, the analysis of the cytokines in the serum of the persistently infected seronegative women revealed that the latter hypo-expresses the cytokine IL-4. Since the molecular events during HIV-1 infection are associated with a marked increase in the levels of IL-4 and IgE in the sera of the infected individuals, it suggests that AIDS is an allergy. Thus, a very low level of IL-4 production may abrogate the virus infection. Studies on the human IL-4 gene revealed that together with the IL-4 mRNA a spliced variant with a deletion of exon 2 is synthesized. The latter is a natural antagonist of IL-4 and when expressed in an individual at a level higher than IL-4, the person will resist a microbial infection (e.g. Mycobacterium tuberculosis) or asthma. The present hypothesis suggests that the HIV-1 resistant APSWs produce more IL-4 delta 2 molecules than IL-4 molecules. The binding of IL-4 delta 2 to IL-4 receptors on T and B cells prevents their functions and the infection by HIV-1. The implications of these studies are that treatment of HIV-1 infected people with drugs that will block the IL-4 receptors will stop HIV-1 infections and the determination of the levels of IL-4 and IL-4 delta 2 in the sera of HIV-1+ patients will enable to identify the individuals that have a natural resistance to HIV-l/AIDS and those who need treatments.

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“…Interferon regulatory factor 1 (IRF-1), the first-identified member of the IRF family, was originally defined as a transcription regulator of IFN-b (Fujita et al 1989(Fujita et al , 1988. Later studies showed that IRF-1 function was not restricted to the IFN pathway but, rather, by binding an interferonstimulated response element (ISRE) present in the promoters of IFN-stimulated genes (ISG), IRF-1 could regulate multiple immune genes' expression and is broadly involved in both innate and adaptive immunity, especially in the regulation of Th1/Th2 differentiation, which may affect resistance to HIV-1 infection (Kroger et al 2002;Lohoff et al 1997;Mamane et al 1999;Taki et al 1997;Taniguchi et al 2001;Trivedi et al 2001). The human IRF-1 gene, spanning 7.72 Kb with its 495 bp immediate upstream promoter sequence, has been assigned to 5q31.1 (Harada et al 1994;Itoh et al 1991).…”

Section: Introductionmentioning

confidence: 99%

Novel interferon regulatory factor-1 polymorphisms in a Kenyan population revealed by complete gene sequencing

Ball

Kimani

et al. 2004

J Hum Genet

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Variation in susceptibility to HIV-1 infection depends on numerous factors, and host genetic variation has been well-described as an important component. As a transcriptional regulator, interferon regulatory factor 1 (IRF-1) plays a key role in both innate and adaptive immunity against viral infection. IRF-1 has also been shown to directly interact with HIV-1 5¢ LTR and efficiently initiate or amplify HIV-1 replication. By complete gene sequencing, we investigated genetic polymorphism of the IRF-1 gene in an HIV-1-endemic Kenyan population. This population displayed extensive genetic diversity at the IRF-1 locus. Fifty-three single nucleotide polymorphisms (SNPs) were identified in this population, including 26 novel SNPs. Two insertion and one deletion polymorphisms in IRF-1 were also identified. Linkage disequilibrium (LD) among these genetic variations was shown to be common in IRF-1. The functional consequences of these mutations in the context of HIV-1/AIDS remain to be determined. We also identified 35 consistent discrepancies between IRF-1 GenBank sequences and our population based sequencing data, suggesting that the previously submitted GenBank data were not representative of the majority of human IRF-1 sequences.

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Resistance to HIV‐1 infection among African sex workers is associated with global hyporesponsiveness in interleukin4 production

Cited by 12 publications

References 56 publications

A Genetic Polymorphism of FREM1 Is Associated with Resistance against HIV Infection in the Pumwani Sex Worker Cohort

A Genetic Polymorphism of FREM1 Is Associated with Resistance against HIV Infection in the Pumwani Sex Worker Cohort

The Molecular Mechanism of Human Resistance to HIV-1 Infectionin Persistently Infected Individuals—A Review, Hypothesis and Implications

Novel interferon regulatory factor-1 polymorphisms in a Kenyan population revealed by complete gene sequencing

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