A potent activator of HIV-1 replication is present in the genital tract of a subset of HIV-1-infected and uninfected women

Spear, Gregory T.; Al‐Harthi, Lena; Sha, Beverly E.; Saarloos, M N; Hayden, Mary K.; Massad, L. Stewart; Benson, Constance A.; Roebuck, Kenneth A.; Glick, Nancy; Landay, Alan

doi:10.1097/00002030-199711000-00005

Cited by 42 publications

(37 citation statements)

References 21 publications

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“…Given the polymicrobial nature of BV, we cannot attribute the stimulatory effects of the CVLs to a specific bacterium or specific bacterial product. However, taken together, our previous observation that the HIV-LTR-inducing activity present in BV CVLs is protease-sensitive as well as the current demonstration that BV CVLs induce HIV LTR activation via TLR2 suggest that at least one of the stimulatory factors present in BV CVLs is either a lipopeptide or a glycoprotein (Spear et al, 1997). Although the TLR2/CD14 cell line experiments demonstrate that BV CVLs stimulate via TLR2, the role of CD14 in this stimulation has not been directly addressed by our studies.…”

Section: Discussionmentioning

confidence: 65%

TLR2-Mediated Cell Stimulation in Bacterial Vaginosis

Mares¹,

Simões²,

Novak³

et al. 2008

Journal of Lower Genital Tract Disease

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Bacterial vaginosis (BV) is associated with preterm labor, pelvic inflammatory disease and increased HIV acquisition, although the pathways that mediate these pathological effects have not been elucidated. To determine the presence of toll-like receptor (TLR)-ligands and their specificity in BV, genital tract fluids were collected from women with and without BV by cervicovaginal lavage (CVL). The CVL samples were evaluated for their ability to stimulate secretion of proinflammatory cytokines and to activate NF κB and the HIV long terminal repeat (LTR), indicators of TLR activation, in human monocytic cells. Stimulation with BV CVLs induced higher levels of IL-8 and TNFα secretion, as well as higher levels of HIV LTR and NF κB activation, than CVLs from women with normal healthy bacterial flora. To identify which TLRs were important in BV, 293 cells expressing specific TLRs were exposed to CVL samples. BV CVLs induced higher IL-8 secretion by cells expressing TLR2 than CVLs from women without BV. Surprisingly, BV CVLs did not stimulate cells expressing TLR4/MD2, although these cells responded to purified LPS, a TLR4 ligand. BV CVLs, in cells expressing TLR2, also activated the HIV LTR. Thus, these studies show that soluble factor(s) present in the lower genital tract of women with BV activate cells via TLR2, identifying a pathway through which BV may mediate adverse effects.

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Section: Discussionmentioning

confidence: 65%

TLR2-Mediated Cell Stimulation in Bacterial Vaginosis

Mares¹,

Simões²,

Novak³

et al. 2008

Journal of Lower Genital Tract Disease

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“…If distinct viral evolution occurs in the PBMC and mucosal compartment, then viral factors could potentially explain the high mucosal susceptibility to HIV and SIV. Since viral replication and therefore genotypic evolution are driven by the inflammatory state of the infected cell, the dynamic inflammatory environment of the gastrointestinal mucosa may drive viral evolution to a greater extent than is seen in the peripheral blood compartment (41). Enhanced viral evolution at an inflamed mucosal site was suggested by Panther et al, who showed greater env heterogeneity in the female genital tract compared to paired blood samples (33).…”

Section: Ccr5mentioning

confidence: 99%

A Preponderance of CCR5⁺CXCR4⁺Mononuclear Cells Enhances Gastrointestinal Mucosal Susceptibility to Human Immunodeficiency Virus Type 1 Infection

Poles¹,

Elliott²,

Taing³

et al. 2001

J Virol

153

106

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The gastrointestinal mucosa harbors the majority of the body's CD4؉ cells and appears to be uniquely susceptible to human immunodeficiency virus type 1 (HIV-1) infection. We undertook this study to examine the role of differences in chemokine receptor expression on infection of mucosal mononuclear cells ( , while these cells make up less than 20% of the peripheral blood cells. It is this cell population that is most susceptible to infection with both R5-and X4-tropic HIV-1 in both compartments. Regardless of whether viral isolates were derived from the blood or mucosa of HIV-1-infected patients, HIV-1 p24 production was greater in MMCs than in PBMCs. Further, the chemokine receptor tropism of these patient-derived viral isolates did not differ between compartments. We conclude that, based on these findings, the gastrointestinal mucosa represents a favored target for HIV-1, in part due to its large population of CXCR4 ؉ CCR5 ؉ target cells and not to differences in the virus that it contains.

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“…Consequently, vaginal secretions contain factors that may affect the infectiousness of HIV-1, as well as the ability to detect infectious virus. Although multiple factors in the vaginal tract could affect the MAGI assay (4,12,39,40), we were unable to demonstrate any effect on MAGI plaque formation with vaginal lavages from HIV-1-uninfected women or the addition of immune factors (proinflammatory cytokines and cathepsin D) often found in genital secretions. Other studies have indicated that GTIs such as bacterial vaginosis and infection with T. vaginalis may be associated with HIV-1 shedding and transmission.…”

Section: Fig 2 Analysis Of the Recovery Of Cell-free Infectious Virmentioning

confidence: 60%

“…To determine whether the number of MAGI plaques is proportional to the amount of infectious HIV- (2,4,12,39,40). To determine whether factors in normal vaginal lavages affect the MAGI assay, aliquots from 10 HIV-1-uninfected women were filtered and used in the MAGI assay in the absence of virus.…”

Section: Resultsmentioning

confidence: 99%

“…The addition of a centrifugation step for concentration of the virus after filtration decreased the number of MAGI plaques by approximately twofold compared to the samples that were only filtered (Table 1). Therefore, all lavage samples were processed through a premoistened 0.45-m filter before being used in subsequent MAGI assays.To determine whether the number of MAGI plaques is Several studies have shown that factors in genital secretions may inhibit or enhance HIV-1 replication in vitro (2,4,12,39,40). To determine whether factors in normal vaginal lavages affect the MAGI assay, aliquots from 10 HIV-1-uninfected women were filtered and used in the MAGI assay in the absence of virus.…”

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confidence: 99%

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Detection of Infectious Human Immunodeficiency Virus Type 1 in Female Genital Secretions by a Short-Term Culture Method

et al. 2003

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Infectious human immunodeficiency virus type 1 (HIV-1) is difficult to detect in female genital secretions by standard virus culture techniques. To improve detection of cell-free HIV-1 in female genital secretions, we adapted a short-term assay that uses the multinuclear-activation galactosidase indicator (MAGI) assay. When vaginal lavages from HIV-1-infected women were tested with the adapted MAGI assay, 25 (64%) of 39 lavages with detectable, cell-free HIV-1 RNA were shown to have infectious virus. No infectious virus was found in 10 vaginal lavages from HIV-1-infected women with undetectable vaginal viral loads. Significantly (P < 0.01) more lavages from HIV-1-infected women tested positive for infectious virus by the MAGI assay than by standard peripheral blood mononuclear cell (PBMC) coculture, which detected infectious virus in only 6 (17%) of 35 vaginal lavages. Lavages with viral loads of >10,000 copies per lavage yielded significantly (P < 0.01) more positive cultures than those with <10,000 copies by using the MAGI assay. Detection of infectious HIV-1 in vaginal lavages was not associated with the presence of genital tract infections or CD4؉ -T-cell counts. However, although the results were not significant (P ‫؍‬ 0.08), the MAGI assay detected infectious virus from more vaginal lavages at a vaginal pH of >4.5 than at a pH of <4.5. These results indicate that the MAGI assay is more sensitive than PBMC culture methods for detecting infectious virus in female genital secretions. Accurate measurements of infectious virus in genital secretions will improve studies that evaluate sexual transmission of HIV-1.The majority of human immunodeficiency virus type 1 (HIV-1) infections worldwide continue to occur through heterosexual transmission (7,27). Factors that influence the amount of HIV-1 in vaginal secretions are important risk determinants for this mode of transmission. It is reported that the amount of HIV-1 RNA in vaginal secretions is correlated with that in plasma (8,13,17,20) and that an increase in plasma viral load in infected persons is associated with an increase in HIV-1 transmission to their sex partners (15,30,35). In addition, localized cervical inflammation and ulceration, without affecting the plasma viral load, can increase HIV-1 shedding in the female genital tract and thus influence HIV-1 transmission (3,22,24,47). Altogether, these studies suggest that increased HIV-1 shedding in mucosal secretions would lead to increased transmission; however, little information is available regarding the presence of infectious virus in cervicovaginal secretions.Several studies have attempted to evaluate infectious HIV-1 in genital secretions by using virus culture methods that are highly successful for propagating virus from an infected person's peripheral blood mononuclear cells (PBMCs). However, use of these methods to culture infectious virus from female genital tract cells has had an overall low success rate (ϳ30%) (18,29,(44)(45)(46). Moreover, recovery of infectious cell-free virus from genital s...

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A potent activator of HIV-1 replication is present in the genital tract of a subset of HIV-1-infected and uninfected women

Cited by 42 publications

References 21 publications

TLR2-Mediated Cell Stimulation in Bacterial Vaginosis

TLR2-Mediated Cell Stimulation in Bacterial Vaginosis

A Preponderance of CCR5⁺CXCR4⁺Mononuclear Cells Enhances Gastrointestinal Mucosal Susceptibility to Human Immunodeficiency Virus Type 1 Infection

Detection of Infectious Human Immunodeficiency Virus Type 1 in Female Genital Secretions by a Short-Term Culture Method

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A potent activator of HIV-1 replication is present in the genital tract of a subset of HIV-1-infected and uninfected women

Cited by 42 publications

References 21 publications

TLR2-Mediated Cell Stimulation in Bacterial Vaginosis

TLR2-Mediated Cell Stimulation in Bacterial Vaginosis

A Preponderance of CCR5+CXCR4+Mononuclear Cells Enhances Gastrointestinal Mucosal Susceptibility to Human Immunodeficiency Virus Type 1 Infection

Detection of Infectious Human Immunodeficiency Virus Type 1 in Female Genital Secretions by a Short-Term Culture Method

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A Preponderance of CCR5⁺CXCR4⁺Mononuclear Cells Enhances Gastrointestinal Mucosal Susceptibility to Human Immunodeficiency Virus Type 1 Infection