Multisite Comparison of Anti-Human Immunodeficiency Virus Microbicide Activity in Explant Assays Using a Novel Endpoint Analysis

Richardson-Harman, Nicola; Lackman-Smith, Carol; Fletcher, Patricia; Anton, Peter A.; Bremer, James W.; Dezzutti, Charlene S.; Elliott, Julie; Grivel, Jean‐Charles; Guenthner, Patricia C.; Gupta, Phalguni; Jones, Maureen; Lurain, Nell S.; Margolis, Leonid; Mohan, Swarna; Ratner, Deena; Reichelderfer, Patricia; Roberts, Paula; Shattock, Robin J.; Cummins, James E.

doi:10.1128/jcm.00673-09

Cited by 49 publications

(51 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…38,39 Of the over 1,200 Boolean categorical comparisons generated, less than 1% showed statistically significant differences between FOL and LUT phases. Table 2 demonstrates that there were no significant differences in vaginal immune cell populations, vaginal histology, vaginal pH, vaginal Nugent score, antimicrobial activity of the CVL, or p24 antigen production from vaginal or ectocervical tissues obtained in the FOL phase versus the LUT phase, adjusting for patient race, contraceptive/sexual prac- Comparison of gene expression profiles in vaginal tissues at FOL and LUT phases revealed only one gene to be differentially expressed (FDR-corrected p-value <.05, fold change ‡2 as described in the Methods section) (heat map for 2,295 genes shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To achieve normality, data were log transformed, as indicated, for the analyses of p24 production and immune cell types as has been previously done. 38,39 For the analyses of p24 antigen production, categorization of infected versus not infected samples was done using 0.1 log steps and a Boolean method, followed by comparison of infected versus not infected samples by Fisher's exact test or McNemar's statistic as appropriate. 40 Log transformation of the antimicrobial data could not be performed because some of the data points were negative numbers.…”

Section: Hiv-1 P24 Antigen Production From Ectocervical or Vaginal Timentioning

confidence: 99%

See 1 more Smart Citation

Comparison of Follicular and Luteal Phase Mucosal Markers of HIV Susceptibility in Healthy Women

Thurman

Chandra

Yousefieh

et al. 2016

AIDS Research and Human Retroviruses

Self Cite

View full text Add to dashboard Cite

The purpose of this study was to evaluate differences in vaginal immune cell populations, vaginal tissue gene expression, antimicrobial activity of the cervicovaginal (CV) lavage (CVL), vaginal flora, and p24 antigen production from CV tissues after ex vivo human immunodeficiency virus (HIV) infection between follicular (FOL) and luteal (LUT) phases of the menstrual cycle. CV tissue biopsies, CV secretions, and blood samples were obtained as part of two longitudinal clinical trials of healthy women (CONRAD D11-119 and A12-124 studies). Participants (n = 39) were HIV-seronegative women not using exogenous hormone supplementation, with normal menstrual cycles, who were screened to exclude sexually transmitted and reproductive tract infections. Serum levels of estradiol and progesterone were significantly higher in the LUT versus the FOL phase of the menstrual cycle. Controlling for race, reported contraceptive use/sexual practices, and clinical trial, we found no differences in vaginal tissue immune cell populations and activation status, transcriptomes, inhibition of HIV, herpes simplex virus type 2 and Escherichia coli by the CVL, vaginal pH or Nugent score, or production of p24 antigen after ex vivo infection by HIV-1 BaL between CV samples obtained in the FOL phase versus the LUT phase of the menstrual cycle. There were no significant correlations between serum estradiol and progesterone levels and CV endpoints. The hypothesis that the LUT phase of the menstrual cycle represents a more vulnerable stage for mucosal infection with HIV was not supported by data from samples obtained from the lower genital tract (ectocervix and vagina) from these two clinical trials.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Hiv-1 P24 Antigen Production From Ectocervical or Vaginal Timentioning

confidence: 99%

Comparison of Follicular and Luteal Phase Mucosal Markers of HIV Susceptibility in Healthy Women

Thurman

Chandra

Yousefieh

et al. 2016

AIDS Research and Human Retroviruses

Self Cite

View full text Add to dashboard Cite

show abstract

“…Infection (individual replicate wells) was monitored with the RETROtek SIV p27 antigen enzyme-linked immunosorbent assay (ELISA) kit (ZeptoMetrix, Buffalo, NY) with a detection limit of 62.5 pg/ml. p27 cumulative (CUM) and soft (SOFT) endpoint analyses (23,24) were performed from 3 days to 14 days of culture because day 0 data represent carryover input virus.…”

Section: Methodsmentioning

confidence: 99%

MIV-150-Containing Intravaginal Rings Protect Macaque Vaginal Explants against SHIV-RT Infection

Ouattara

Barnable

Mawson

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

“…The soft (SOFT) and cumulative (CUM) analyses were performed as described previously in references 33, 39, and 40 using a template from Alpha StatConsult LLC. Briefly, SOFT is a cross-sectional index from a growth curve that is reflective of the virus growth achieved in the assay (39,40). CUM is the cumulative readout of infection (days 3 to 14) (39).…”

Section: Macaquesmentioning

confidence: 99%

MIV-150/Zinc Acetate Gel Inhibits Cell-Associated Simian-Human Immunodeficiency Virus Reverse Transcriptase Infection in a Macaque Vaginal Explant Model

Barnable

Calenda

Bonnaire

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The transmission of both cell-free and cell-associated immunodeficiency viruses has been demonstrated directly in multiple animal species and possibly occurs in humans, as suggested by genotyping of the infecting human immunodeficiency virus (HIV) in acutely infected women and in semen from their partners. Therefore, a microbicide may need to block both mechanisms of HIV transmission to achieve maximum efficacy. To date, most of the preclinical evaluation of candidate microbicides has been performed using cell-free HIV. New models of mucosal transmission of cell-associated HIV are needed to evaluate candidate microbicide performance. The MIV-150/zinc acetate/carrageenan (MZC) gel protects Depo-Provera-treated macaques against cell-free simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) infection when applied vaginally up to 8 h before challenge. We recently demonstrated the potent activity of MZC gel against cell-free SHIV-RT in macaque vaginal explants. In the current study, we established a cell-associated SHIV-RT infection model of macaque vaginal tissues and tested the activity of MZC gel in this model. MZC gel protected tissues against cell-associated SHIV-RT infection when present at the time of viral exposure or when applied up to 4 days prior to viral challenge. These data support clinical testing of the MZC gel. Overall, our ex vivo model of cell-associated SHIV-RT infection in macaque vaginal mucosa complements the cell-free infection models, providing tools for prioritization of products that block both modes of HIV transmission. Women account for about half of human immunodeficiency virus type 1 (HIV-1) infections, with the majority of infections transmitted via sexual intercourse (1). A longitudinal study reported that the genotype of the infecting HIV-1 in acutely infected women closely matches the virus in the seminal plasma and seminal cells from their chronically infected sexual partners (2), suggesting that transmission of both cell-free and cell-associated HIV-1 occurs in vivo. Furthermore, transmitter/founder donor variants were identified in peripheral blood mononuclear cells (PBMCs) and blood plasma, also suggesting that both cell-free transmission and cell-associated HIV transmission occur in vivo (3, 4). Which mode of transmission has a primary role in the establishment of mucosal infection is yet to be determined (5).Cell-to-cell HIV transmission is associated with efficient in vitro viral transfer through virological synapses (6-9). Cell-associated HIV was shown to pass the epithelial monolayer and infect the underlying target cells in vitro (10, 11). In agreement with this information, seminal cells (12) and macrophages (13) were shown to penetrate the epithelium in cervical explant tissues and thus could potentially deliver HIV to target cells. Recent studies mimicking HIV transmission in the intestinal tract in a rectal explant model revealed that ex vivo transmission of cell-associated simian immunodeficiency virus (SIV mac251 ) is more efficient than transmission o...

show abstract

Multisite Comparison of Anti-Human Immunodeficiency Virus Microbicide Activity in Explant Assays Using a Novel Endpoint Analysis

Cited by 49 publications

References 29 publications

Comparison of Follicular and Luteal Phase Mucosal Markers of HIV Susceptibility in Healthy Women

Comparison of Follicular and Luteal Phase Mucosal Markers of HIV Susceptibility in Healthy Women

MIV-150-Containing Intravaginal Rings Protect Macaque Vaginal Explants against SHIV-RT Infection

MIV-150/Zinc Acetate Gel Inhibits Cell-Associated Simian-Human Immunodeficiency Virus Reverse Transcriptase Infection in a Macaque Vaginal Explant Model

Contact Info

Product

Resources

About