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Due to the stringent population bottleneck that occurs during sexual HIV-1 transmission, systemic infection is typically established by a limited number of founder viruses. Elucidation of the precise forces influencing the selection of founder viruses may reveal key vulnerabilities that could aid in the development of a vaccine or other clinical interventions. Here, we utilize deep sequencing data and apply a genetic distance-based method to investigate whether the mode of sexual transmission shapes the nascent founder viral genome. Analysis of 74 acute and early HIV-1 infected subjects revealed that 83% of men who have sex with men (MSM) exhibit a single founder virus, levels similar to those previously observed in heterosexual (HSX) transmission. In a metadata analysis of a total of 354 subjects, including HSX, MSM and injecting drug users (IDU), we also observed no significant differences in the frequency of single founder virus infections between HSX and MSM transmissions. However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants. Moreover, specific genetic "signatures" within MSM and HSX founder viruses were identified, with single polymorphisms within gp41 enriched among HSX viruses while more complex patterns, including clustered polymorphisms surrounding the CD4 binding site, were enriched in MSM viruses. While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition. This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission.

Background: Pelvic floor dysfunction is a group of disorders that can significantly impact quality of life due to persistent urinary and anal incontinence. Data evaluating the effect of prolonged second stage of labor and postpartum pelvic floor dysfunction is heterogenous and limited. Objective To evaluate whether extending the length of labor in nulliparous women with prolonged second stage affects the presence of self-reported pelvic floor dysfunction after a randomized controlled trial of prolonged second stage. Study design We conducted a planned follow up survey to our randomized controlled trial of prolonged second stage of labor using the Pelvic Floor Distress Inventory-20 (PFDI-20). The primary outcome was the PFDI-20 summary score. Secondary outcomes included urinary and fecal incontinence, prolapse, and patient satisfaction. Women surveyed were nulliparous patients with epidural anesthesia, previously enrolled in a randomized controlled trial that assigned them to extended labor, at least 1 additional hour in the second stage if they were undelivered after three hours, or to usual labor, defined as expedited delivery after three hours in the second stage. Women were surveyed at 12 − 36 months postpartum. Results Thirty-four of the seventy-eight women responded to the survey (43.6%). 17 women (50.0%) were from the extended labor group and 17 from the usual labor group (50.0%). Maternal demographic data were not significantly different between groups. The PFDI-20 summary score was 13.8 ± 23.3 in the extended labor group and 13.1 ± 20.9 in the usual labor group (p = 0.9). The Pelvic Organ Prolapse Distress Inventory-6 was 1.2 ± 2.9 in the extended labor group and 2.7 ± 6.4 in the usual labor group (p = 0.4). The Colorectal-Anal Distress Inventory-8 was 0.8 ± 2.8 in the extended labor group and 2.1 ± 4.0 in the usual labor group (p = 0.6). The Urinary Distress Inventory-6 was 11.8 ± 21.1 in the extended labor group and 8.3 ± 14.5 in the usual labor group (p = 0.6). Maternal and neonatal outcomes, as well as patient satisfaction, were not statistically significantly different between groups. Conclusion Extending the length of labor in nulliparas with singleton gestations, epidural anesthesia, and prolonged second stage did not have an impact on PFDI-20 scores at 12–36 months postpartum. However, our study was underpowered to detect small, but potentially clinically important, differences. [ABSTRACT FROM AUTHOR]

The acquisition and maintenance of NK-cell function is mediated by inhibitory killer-cell immunoglobulin-like receptors (KIRs) through their interaction with HLA class I molecules. Recently, HLA-C expression levels were shown to be correlated with protection against multiple outcomes of HIV-1 infection; however, the underlying mechanisms are poorly understood. As HLA-C is the natural ligand for the inhibitory receptors KIR2DL1 and KIR2DL2/3, we sought to determine whether HLA-C group haplotypes affect NK-cell responses during primary HIV-1 infection. The phenotypes and functional capacity of NK cells derived from HIV-1-positive and HIV-1-negative individuals were assessed ( N = 42 and N = 40, respectively). HIV-1 infection was associated with an increased frequency of KIR2DL1-3+ NK cells. Further analysis showed that KIR2DL1+ NK cells were selectively increased in individuals homozygous for HLA-C2, while HLA-C1-homozygous individuals displayed increased proportions of KIR2DL2/3+ NK cells. KIR2DL1-3+ NK cells were furthermore more polyfunctional during primary HIV-1 infection in individuals also encoding for their cognate HLA-C group haplotypes, as measured by degranulation and IFN-γ and TNF-α production. These results identify a novel relationship between HLA-C and KIR2DL+ NK-cell subsets and demonstrate that HLA-C-mediated licensing modulates NK-cell responses to primary HIV-1 infection. [ABSTRACT FROM AUTHOR]

Due to the stringent population bottleneck that occurs during sexual HIV-1 transmission, systemic infection is typically established by a limited number of founder viruses. Elucidation of the precise forces influencing the selection of founder viruses may reveal key vulnerabilities that could aid in the development of a vaccine or other clinical interventions. Here, we utilize deep sequencing data and apply a genetic distance-based method to investigate whether the mode of sexual transmission shapes the nascent founder viral genome. Analysis of 74 acute and early HIV-1 infected subjects revealed that 83% of men who have sex with men (MSM) exhibit a single founder virus, levels similar to those previously observed in heterosexual (HSX) transmission. In a metadata analysis of a total of 354 subjects, including HSX, MSM and injecting drug users (IDU), we also observed no significant differences in the frequency of single founder virus infections between HSX and MSM transmissions. However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants. Moreover, specific genetic “signatures” within MSM and HSX founder viruses were identified, with single polymorphisms within gp41 enriched among HSX viruses while more complex patterns, including clustered polymorphisms surrounding the CD4 binding site, were enriched in MSM viruses. While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition. This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission.

An abstract of the article "Protective Role of TLR3 Induced Human Beta Defensins during Acute HIV-1 Infection" by Bjorn Corleis, Antonella Lisanti, Christian Korner, and colleagues is presented.

An abstract of the article "Genetic Footprints within the HIV-1 Envelope Glycoprotein Associated with Transmission in Men Who Have Sex with Men" by Damien C. Tully and colleagues is presented.

The acquisition and maintenance of NK-cell function is mediated by inhibitory killer-cell immunoglobulin-like receptors (KIRs) through their interaction with HLA class I molecules. Recently, HLA-C expression levels were shown to be correlated with protection against multiple outcomes of HIV-1 infection; however, the underlying mechanisms are poorly understood. As HLA-C is the natural ligand for the inhibitory receptors KIR2DL1 and KIR2DL2/3, we sought to determine whether HLA-C group haplotypes affect NK-cell responses during primary HIV-1 infection. The phenotypes and functional capacity of NK cells derived from HIV-1-positive and HIV-1-negative individuals were assessed (N = 42 and N = 40, respectively). HIV-1 infection was associated with an increased frequency of KIR2DL1-3(+) NK cells. Further analysis showed that KIR2DL1(+) NK cells were selectively increased in individuals homozygous for HLA-C2, while HLA-C1-homozygous individuals displayed increased proportions of KIR2DL2/3(+) NK cells. KIR2DL1-3(+) NK cells were furthermore more polyfunctional during primary HIV-1 infection in individuals also encoding for their cognate HLA-C group haplotypes, as measured by degranulation and IFN-γ and TNF-α production. These results identify a novel relationship between HLA-C and KIR2DL(+) NK-cell subsets and demonstrate that HLA-C-mediated licensing modulates NK-cell responses to primary HIV-1 infection., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)