Non-Cationic Proteins Are Associated with HIV Neutralizing Activity in Genital Secretions of Female Sex Workers

Abstract

ObjectiveCationic proteins found in cervicovaginal secretions (CVS) are known to contribute to the early antiviral immune response against HIV-infection in vitro. We here aimed to define additional antiviral factors that are over-expressed in CVS from female sex workers at high risk of infection.MethodsCVS were collected from Kenyan HIV-seronegative (n = 34) and HIV-seropositive (n = 12) female sex workers, and were compared with those from HIV-seronegative low-risk women (n = 12). The highly exposed seronegative (HESN) sex workers were further divided into those with less (n = 22) or more (n = 12) than three years of documented sex work. Cationic protein-depleted CVS were assessed for HIV-neutralizing activity by a PBMC-based HIV-neutralizing assay, and then characterized by proteomics.ResultsHIV neutralizing activity was detected in all unprocessed CVS, however only CVS from the female sex worker groups maintained its HIV neutralizing activity after cationic protein-depletion. Differentially abundant proteins were identified in the cationic protein-depleted secretions including 26, 42, and 11 in the HESN>3yr, HESN<3yr, and HIV-positive groups, respectively. Gene ontology placed these proteins into functional categories including proteolysis, oxidation-reduction, and epidermal development. The proteins identified in this study include proteins previously associated with the HESN phenotype in other cohorts as well as novel proteins not yet associated with anti-HIV activities.ConclusionWhile cationic proteins appear to contribute to the majority of the intrinsic HIV neutralizing activity in the CVS of low-risk women, a broader range of non-cationic proteins were associated with HIV neutralizing activity in HESN and HIV-positive female sex workers. These results indicate that novel protein factors found in CVS of women with high-risk sexual practices may have inherent antiviral activity, or are involved in other aspects of anti-HIV host defense, and warrant further exploration into their mode of action.

Unique Insights in the Cervicovaginal Lactobacillus iners and L. crispatus Proteomes and Their Associations with Microbiota Dysbiosis

“…Search parameters were as follows: precursor mass tolerance 10 ppm, fragment mass tolerance 0.6 Da, false discovery rate <1%, and individual ion scores >13 (indicating identity or extensive homology at p<0.05). Only bacterial proteins for which at least one unique peptide and at least two peptides overall (including non-unique peptides) were identified were included in further analyses, as has been done in previous cervicovaginal studies [ 14 – 16 ]. Furthermore, L .…”

The relationship between sex hormones, the vaginal microbiome and immunity in HIV-1 susceptibility in women

“…These form a hydrophobic layer of mucus that traps pathogens and prevents access to the underlying epithelial cells ( Lai et al, 2009 ; Quayle, 2002 ; Shukair et al, 2013 ). In addition to mucins, the vaginal mucus contains other host defense molecules, including antimicrobial peptides (AMPs; Box 1 ) and complement system components, which can directly bind to and eliminate pathogens, impeding access to the vaginal epithelium ( Birse et al, 2015b ; Quayle, 2002 ). These protective features can effectively dampen HIV-1 motility in human cervicovaginal mucus and enhance vaginal barrier function ( Shukair et al, 2013 ).…”

Role of Different Subpopulations of CD8+ T Cells during HIV Exposure and Infection

“…Some genetic and immunological mechanisms have been associated with the resistant phenotype as follows: (i) genetic polymorphisms in the required co-receptors for viral entry, such as CCR5 or CCR2 ( 5 , 6 ); (ii) increased production of the co-receptor ligands MIP-1α/β, RANTES or SDF-1; (iii) the presence of antibodies blocking viral co-receptors ( 7 ); (iv) the expression of different microRNAs induced by the viral exposure ( 8 , 9 ) that may modulate the innate immune system or interfere directly with viral mRNAs blocking the infection ( 10 ); (v) induction of spontaneous apoptosis of target cells ( 6 , 11 ); (vi) production of soluble factors with antiviral activity, such as TRIM5α, APOBEC-3G, SAMHD-1, serpina1, elafin, Human neutrophil peptide, beta-defensins, and LL-37 ( 12 – 14 ), other proteins implicated in host defense and bacterial binding, such as bPRP2, Histatin-3, Lysozyme C, and SLPI ( 15 ), and the presence of non-cationic proteins in genital secretions with HIV-1 neutralizing activity ( 16 ); (vii) high activity of natural killer cells ( 17 , 18 ) and dendritic cells (DC) ( 19 ); (viii) high levels of neutralizing IgA antibodies ( 18 , 20 ), which are even associated with protection in vaccine clinical trials, as they could prevent HIV mucosal transcytosis ( 21 ); (ix) expression of the alleles HLA-B57 and -B27 that present immunodominant peptides ( 6 ); and (x) effective and polyfunctional profile of HIV-specific CD4 + and CD8 + T cell responses ( 22 , 23 ).…”