HNPs1-3
The role of HNPs in HIV pathogenesis was first suggested by the association made between HNPs 1-3 and soluble anti-HIV activity of CD8+ T cells (CAF) isolated from patients infected with HIV but remaining free of AIDS for a prolonged period (long-term nonprogressors, LTNPs) [110].
These peptides were detected in the media of stimulated CD8+ T cells from normal healthy controls and LTNPs but not from HIV progressors. Subsequent studies on the cell source of defensins revealed that HNPs were probably produced by co-cultured monocytes and residual granulocytes of allogenic normal donor irradiated PBMCs that were used as feeder cells, but they were not produced by the CD8+ T cells themselves [26, 27], suggesting uptake might differ between the groups studied. Using similar co-culture systems, levels of HNPs1-3 were measured in CD8+ T- cell supernatants and cervical-vaginal mononuclear cells (CVMCs) derived from HIV-exposed seronegative individuals, HIV-infected patients, and normal controls [130]. Higher levels of HNPs were found in CD8+ T cells from HIV-exposed seronegative individuals and HIV patients compared to normal controls.An association between production of HNPs 1-3 in breast milk and transmission of HIV has also been reported [131]. In a case-controlled study of HIV-positive women, levels of HNPs in breast milk correlated with HIV RNA copy number in breast milk, which was a strong predictor of transmission. However, after adjusting for breast milk HIV copy number, higher levels of HNPs in breast milk were associated with a decreased incidence of intrapartum or postnatal HIV transmission. Bosire and colleagues performed similar studies to determine the correlation between HNPs in breast milk and transmission risk in a cohort of 260 HIV-1- infected pregnant women in Nairobi followed for 12 months postpartum with their infants [132].
Analysis of breast milk from these women at one month postpartum demonstrated that women with detectable HNPs1-3 had significantly higher mean breast milk HIV-1 RNA levels than women with undetectable α-defensins. Increased α-defensin concentrations in breast milk were also associated with subclinical mastitis and increased CC-chemokines in breast milk. Interestingly, in contrast to the report by Kuhn et al. [131], the level of defensins was not associated with vertical transmission, indicating a complex interplay between innate effectors, inflammation and HIV transmission.There is a correlation between the abundance of several anti-HIV proteins, including HNPs1-3 and cell- associated HIV replication in lymphoid follicles compared with extrafollicular lymphoid tissue [133]. Expression of these antiviral proteins is significantly lower in the follicular region, where HIV replication is concentrated, compared with the extrafollicular regions in lymph nodes from HIV-positive individuals.
Cationic peptides including defensins are associated with anti-HIV activity of vaginal fluid from healthy women [134]. While it is well established that sexual transmitted infections (STIs) significantly increase the
likelihood of HIV transmission [135-139] and that levels of defensins including HNPs, HBDs and HD5 in genital fluid, are elevated in patients with STIs [10, 31-33], the role of defensins in HIV transmission seems to be quite complex. A study involving a cohort of HIV uninfected sex workers in Kenya demonstrated an association between an increase in HNPs and LL-37 levels in the IgA-depleted Cervicovaginal secretions from women with bacterial STIs and increased in HIV acquisition compared to women without STIs. In this case, the high levels of HNPs and LL-37 did not appear to be protective although it is hard to determine if they provide some level of protection in the permissive environment presented by active inflammation associated with an STI [129]. This study underscores the complex role of defensins in HIV transmission at the vaginal mucosa and the urgent need to define the role of innate effectors in HIV acquisition.