X-linked Biological Response to HIV Sensing: the ANRS EP 53 Study (X LIBRIS)

Frequency and Functional Impact of the c.32A>T Genetic Polymorphism of TLR7 in Women Infected With HIV-1 : the ANRS EP53 Study

Short title : X-linked biological response to HIV sensing: the ANRS EP 53 study. Main outcome : To demonstrate that HIV-infected women carry the TLR7 c.32A>T SNP at a higher frequency than uninfected women, arguing in favor of a role of impaired production of IFN-alpha by pDCs in the risk of becoming infected by HIV-1. Secondary outcome : To directly demonstrate at a single cell level that the TLR7 c.32A>T SNP is responsible for a reduce production of IFN-alpha by pDCs after activation of TLR7 by HIV-1 RNA. Short abstract (public dissemination) : Male and female display some differences in how their immune system responds to pathogens. This could be related to hormonal or genetic factors located on the X chromosome. This project aims at characterizing X-linked factors that can influence the innate immune response to HIV-1.

Plasmacytoid dendritic cells (pDCs) are key actors of innate immunity that produce high levels of interferon (IFN)-alpha after activation of their Toll-Like Receptors (TLR) by pathogens. A difference between men and women has recently been shown in the level of IFN-alpha produced by pDCs after TLR activation. The production of IFN-alpha in response to TLR7 activation is higher in the presence of estrogens. This could be responsible for gender differences in the level of plasma HIV-1 RNA, that is lower in female as compared to male by about 50%, and for the sex-based differences in the susceptibility to HIV infection. Besides the role of estrogens, X-linked genetic factors could also be involved in the sex-dependent differences in the TLR7-mediated responses of pDCs. TLR7 gene is located on the X chromosome. A single nucleotide polymorphism (SNP) of the TLR7 gene, c.32A>T, have been associated with accelerated disease progression in male HIV patients, and was found over represented in female HIV as well as HCV patients, suggesting that the T allele is associated with a gender-dependent increase of susceptibility to RNA virus infections. A peripheral blood sample will be collected from HIV-infected women and healthy control to measure TLR-7 SNP frequency by PCR. IFN-alpha production from pDCs after HIV-1 RNA sensing by TLR7 will also be assessed.

A peripheral blood sample will be collected from HIV-infected women to measure TLR-7 SNP frequency by PCR. IFN-alpha production from pDCs after HIV-1 RNA sensing by TLR7 will also be assessed.

A peripheral blood sample will be collected from healthy women to measure TLR-7 SNP frequency by PCR. IFN-alpha production from pDCs after HIV-1 RNA sensing by TLR7 will also be assessed

A peripheral blood sample will be collected from HIV-infected subjects and healthy control to measure TLR-7 SNP frequency by PCR. IFN-alpha production from pDCs after HIV-1 RNA sensing by TLR7 will also be assessed

arguing in favor of role of impaired production of IFN alpha by pDCs in the risk of becoming infected by HIV 1

Frequency (%) of cells expressing the "A" and "T" alleles of TRL7 in interferon-alpha producing cells

Inclusion Criteria: Caucasian Female HIV-1 infection (ELISA and western-blot tests) HIV-infection through the sexual route before 50 years-old Continuous antiretroviral therapy for more than 6 months Plasma HIV-1 RNA <50 copies/ml in the last 6 months Age >18-year old Health insurance Informed consent Exclusion Criteria: HIV-infection through vertical or parenteral routes Chronic infectious disease, notably HCV infection (hepatitis C virus) Acute infectious disease Auto-immune disease Absence of social security (health insurance) Pregnant or breastfeeding woman Incapable adult