Dottorato in MALATTIE INFETTIVE, MICROBIOLOGIA E SANITA' PUBBLICA

Titolo della tesi: STATE OF SYSTEMIC, MUCOSAL IMMUNE ACTIVATION AND PSYCHO-SEXUAL HEALTH IN ART SUPPRESSED HIV-INFECTED WOMEN: EVALUATING BIOMARKERS AND ENVIRONMENTAL STIMULI

Background: HIV Infection has been specific in women compared to men since the discovery of HIV and is of sincere concern despite the emergence of progressive ART. Women are more vulnerable to catch infection as compared to men due to several factors such as reproductive, hormonal differences, lifestyle, coinfections and immunity. Hence, analysing biomarkers in the plasma and vaginal lavage, and studying mucosal and systemic immunity, sexual behaviour and vaginal infections to evaluate the elicited immune response in HIV infected ART suppressed women is of utmost significance. Methodology: 58 subjects of similar age, 24 HIV Positive women on successful ART, 34 Healthy women (HD) were enrolled. Nationality, HIV Viremia, HIV RNA, Partner’s HIV Status, Occupation, Stage of Menstrual cycle, initial CD4 count etc were some of the major clinical parameters considered at the time of admission. Generalised Anxiety Disorder (GAD) and Female Sexual Function Index (FSFI) were examined using specific questionnaires. Levels of sex hormones (Testosterone, Estradiol, and Progesterone) were also calculated at the time of enrolment. Women were also tested for Commensal and sexually transmitted microorganisms. Flow Cytometry was performed for the estimation of CD3, CD4, CD8, B cells and NK cells. Kit ELISA (R&D systems) were used for the estimation of cytokines (IL-1Beta, IL-6, IL-8, CxCl10, sCD163, sCD14). Screening for CMV DNA shedding and the presence of antigens indicating Bacterial Vaginosis (BV), HPV. HPV genotyping was pursued after successful detection of HPV DNA. Statistical analysis was performed using PRISM 8. Results: Both groups had similar CD3, CD4 and B lymphocytes. Healthy women had a higher CD4/CD8 ratio and CD8 cell count compared to infected (p<0.0001, p=0.002). Healthy women had higher NK cell count (p=0.0007). Plasma levels of sCD163, IL-1β, IL-6 and IL-8 were significantly higher in HIV women (p=0.008, p=0.02, p=0.0001 and p=0.03,), while IL-6 was lower in the vaginal lavage (p=0.008,) of HIV women. CMV-IgG antibody titer was markedly high in the HIV population (p<0.0001) even if no CMV DNA shedding was observed in the entire population. HIV women revealed a higher prevalence for STM especially for Ureaplasma parvum and Mycoplasma hominis. BV antigens were high in VL of HIV women (p=0.02). Regarding sexual hormonal state we discovered that Testosterone and progesterone were slightly higher in the healthy women (p=0.04 and p=0.03) regardless of age. Estradiol levels positively correlated to plasmatic CXCL-10 (r=0.5, p=0.01) while testosterone levels correlated to CD4/CD8 ratio (r=0.3, p=0.07) in HIV. The FSFI score was significantly lower in the HIV group (p=0.03), specifically for sexual desire(p=0.004) and lubrication (p=0.01). Testosterone and estradiol levels positively correlated to FSFI in HIV women (r= 0.56, p=0.02 and r=0.51, p=0.02). Both groups showed similar anxiety disorder. Conclusion: HIV positive women on effective therapy still show signs of immuno-inflammation both at the plasmatic and mucosal levels, with a disturbed sexual health. Hormone levels of estradiol and testosterone were associated with a more favorable pattern in terms of immune- inflammation and sexual health. With an effective use of ART HIV women too can enjoy an immunological status which is equivalent to that of healthy women. A higher IgG titre for CMV was seen in HIV patients. Further studies will be necessary to evaluate possible interventions aimed at improving these parameters in order to remove the obstacles to a true "normalization" of the quality of life of the HIV-infected woman.