Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Opin HIV AIDS. Author manuscript; available in PMC 2009 September 1.
Published in final edited form as:
Curr Opin HIV AIDS. 2008 September; 3(5): 541–547.
doi:  10.1097/COH.0b013e32830ab9ee
PMCID: PMC2659331

Mucosal Immunity to HIV: A Review of Recent Literature


Purpose of review

This review summarizes recent literature in the field of mucosal immunology as it applies to human immunodeficiency virus (HIV) transmission and pathogenesis.

Recent findings

Pertinent recent findings include elucidation of the role of mucosal antigen-presenting cells and retinoic acid in imprinting a gut-homing phenotype on antigen-specific T and B cells, and the identification of Th17 and Treg cells as key modulators of the balance between tolerance and inflammation in mucosal tissues.


Mucosal surfaces of the body serve as the major portal of entry for human immunodeficiency virus (HIV). These tissues also house a majority of the body's lymphocytes, including the CD4+ T-cells that are the major cellular target for HIV infection. Elucidating mucosal immune responses is critical to our understanding of the host-pathogen relationship for two reasons: first, mucosal barriers are defended by a range of innate and adaptive defenses that might be exploited to develop effective vaccines and/or microbicides; second, adaptive immune responses in mucosal lymphoid tissues may serve to limit viral replication, decreasing the host's viral burden as well as reducing the likelihood of sexual transmission to a naïve host.

Keywords: CTL, gut, IgA, Treg, Th17


Mucosal tissues are generally accepted as the largest collection of lymphoid tissues in the body, and the majority of the body's T- and B-lymphocytes are housed in the gastrointestinal mucosa, an assessment based upon enumeration of Peyer's patches and lymphoid follicles in human intestine [1*,2]. The distribution of mucosal tissues throughout the body has recently been reviewed in detail, along with the standardized nomenclature adopted by the Society for Mucosal Immunology [1*].

The genetic and immunologic correlates of protection from human immunodeficiency virus (HIV) infection have still not been fully elucidated. Intensive studies are underway to characterize potentially protective immune responses in relevant cohorts, including HIV Controllers, nonhuman primates with non-progressive simian immunodeficiency virus (SIV) infection, and highly exposed, persistently seronegative (HEPS) individuals [3-5]. Given that the majority of HIV transmission occurs via mucosal surfaces, there is great interest in understanding how the complex interplay of innate and adaptive mucosal defenses may shape the outcome of HIV infection. This review will highlight recent developments in the field of mucosal immunology within the context of HIV/SIV infection.

Recent advances in the field of mucosal immunology

Much remains to be learned about the induction and trafficking patterns of mucosal lymphocytes in humans. Recent advances in murine models have led to a new appreciation for the role of mucosal antigen-presenting cells in imprinting a gut-homing phenotype on antigen-specific lymphocytes. A series of studies demonstrated that rodents deficient in vitamin A have reduced IgA-producing antibody secreting cells (ASC) and effector/memory T cells in intestinal mucosa [6,7]. Retinoic acid (RA), a metabolite of vitamin A, induces expression of integrin α4β7 and chemokine receptor CCR9, which are implicated in lymphocyte homing to the intestinal mucosa [7]. Intestinal dendritic cells (DC) express enzymes critical for RA biosynthesis [7], and deliver the instructive signal triggering expression of α4β7 and CCR9 [8-11] (reviewed in [12]). Intriguingly, the activated α4β7 heterodimer, expressed on gut-homing lymphocytes as they transit through blood, can bind HIV gp120 on infected CD4+ T-cells. The gp120-α4β7 interaction, in turn, triggers activation of αLβ2 integrin (LFA-1) on the CD4+ T-cell surface. LFA-1 is critical for cell-cell interactions and ‘immunological synapse’ formation; accordingly, its upregulation on infected CD4 cells may facilitate cell-to-cell spread of HIV [13**].

Second, renewed attention has been devoted to oral tolerance, and to the balance between tolerogenic and pro-inflammatory T-cell responses in the intestinal mucosa. In the mouse intestine, RA and TGF-β1 induce differentiation of regulatory CD4+ T cells expressing the forkhead box transcription factor FoxP3 [14,15**]. However, in a proinflammatory cytokine environment in which both TGF-β1 and IL-6 are present, the “balance” is tipped in favor of Th17-type responses [15**,16]. Th17 cells are CD4+ T cells whose induction depends on the orphan nuclear receptor RORγt [17*]. These cells express IL-17 and IL-22, and are critical in clearing fungal and extracellular bacterial infections [18**], but can also mediate inflammation and autoimmunity [19]. These findings relate to rodent models for tolerance and inflammation, so their applicability to HIV/SIV infection remains to be determined. Nevertheless, mucosal Treg and Th17 cells have been identified in HIV-infected humans and SIV-infected macaques, as discussed below.

Immune regulation and mucosal tissues: The Th17/Treg balance

Recent reports indicate that Th17 cells are important targets for acute HIV/SIV infection in the GI tract. These cells may be preferentially lost in HIV/SIV-infected hosts with progressive disease [20*-22*], but not in non-progressing hosts such as sooty mangabeys [21*] or African green monkeys [20*]. In addition, SIV-infected rhesus macaques coinfected with S. typhimurium showed increased bacterial dissemination relative to SIV-uninfected controls, coincident with a loss of mucosal Th17 cells [23**]. This finding mirrored the observation that IL-17 receptor deficient mice showed increased systemic dissemination of S. typhimurium from the gut, suggesting that IL-17 deficiency causes defects in mucosal barrier function [23**]. Taken together, these observations suggest a model to explain the mucosal translocation of bacterial products in individuals with HIV/SIV infection [24,25]. Systemic immune activation has been identified as a key feature differentiating pathogenic versus non-pathogenic outcomes of HIV/SIV infection [3].

The role of Treg in HIV/SIV pathogenesis remains less clear; these cells may reduce immune activation, but may also limit HIV-specific adaptive responses [26*]. Treg have been phenotypically identified in blood and mucosal tissues of HIV-infected humans [27,28] and SIV-infected macaques [29,30]. In acute SIV infection, Treg are reportedly expanded in lymph node paracortical regions [29], but depleted from ileal mucosa [31]. In chronic SIV infection, FoxP3 and CTLA-4 mRNA were increased in mucosal tissues of macaques with high viremia, and FoxP3 mRNA correlated with SIV RNA levels in tissues [32*]. Indirect markers for Treg function, including indoleamine 2,3 dioxygenase, were also associated with high viral load. It remains unclear whether the presence of Treg in mucosal tissues simply reflects a consequence of inflammation or whether these cells promote virus replication and dissemination by limiting HIV/SIV-specific adaptive responses.

Acute HIV/SIV infection and the gastrointestinal tract

There is now an extensive literature documenting the rapid depletion of gut lamina propria CD4+ T-cells during acute HIV/SIV infection [33,34]. This depletion may be mediated by direct infection of target cells [35], bystander apoptosis [36], or a combination of mechanisms. Studies of rhesus macaques vaginally exposed to SIVmac revealed that the SIV-specific CD8+ T-cell response in gut occurred “too little and too late” to prevent depletion of lamina propria CD4+ T-cells and systemic viral dissemination [37,38].

Innate immune responses at mucosal surfaces could theoretically provide an important means of limiting HIV replication and dissemination. However, there are few reports describing the role of innate mucosal effector cells in HIV disease. Mucosal NK and NK-T cells have not been extensively studied; one report showed depletion of colonic NK cells in HIV-infected subjects [39]. Similarly, few studies have focused on intestinal γδ T cells in HIV infection [40]. However, one paper reported an expansion of γδ T cells in immunized macaques protected from rectal challenge with SIVmac251 [41]. It was recently demonstrated that sooty mangabeys have a higher frequency of γδ T cells in blood than humans or rhesus macaques [42*]. Although their role in immunosurveillance remains poorly understood, mucosal γδ T cells may limit opportunistic infections and/or maintain intestinal epithelial integrity [40,42*].

Mucosal cell-mediated immunity during chronic infection

In HIV/SIV infection, intestinal lamina propria CD4+ T-cells are rapidly depleted and there is an expansion and/or influx of CD8+ T-cells [43]. The persistence of virus in mucosal tissues throughout chronic infection argues that these tissues remain sites of ongoing interaction between the virus and the immune system. MHC Class I-restricted cytotoxic T cells (CTL) have been identified throughout the gastrointestinal mucosa of individuals with chronic HIV disease [44,45] and SIV-infected rhesus macaques [46,47]. Studies characterizing the TCR hypervariable regions of CTL clones from rectal mucosa, semen and cervix revealed that many such clones were shared between mucosal sites and PBMC [48]. Due to the difficulty of obtaining large numbers of lymphocytes from biopsy tissue, comprehensive mapping of response breadth has been challenging. However, studies to date suggest that CD8+ T-cells from rectal mucosa and blood recognize similar HIV peptide pools [49] and epitopes [50].

Intestinal CD8+ T-cells exhibit a partially activated, effector memory phenotype [51-53]. Despite abundant expression of granzymes, rectal CD8+ T-cells express low levels of perforin as compared to their counterparts in blood [38,54]. Nevertheless, when stimulated in vitro with HIV peptides, rectal CD8+ T-cells produce cytokines and release CD107-containing granules [55*,56*]. One study reported that HIV-specific CD8+ T-cell responses in terminal ileum were weak, in contrast to bronchoalveolar lavage, which contained a high frequency of polyfunctional CD8+ T cells; it remains unclear whether this finding reflects the role of terminal ileum as an inductive site [57*]. Nevertheless, additional studies comparing responses at multiple mucosal sites are warranted. Many “elite controllers”, defined as individuals with chronic HIV infection and plasma viremia <50 copies/mL in the absence of antiretroviral therapy [4], have unusually robust and polyfunctional HIV-specific T-cell responses in rectal mucosa [58*]. Taken together, these findings suggest that MHC-restricted T cells in mucosal tissues serve as a critical component of the host's adaptive immune armamentarium throughout chronic infection.

Mucosal antibodies and HIV transmission

Can mucosal antibodies protect against HIV/SIV transmission? In two landmark studies, systemically administered combinations of neutralizing antibodies protected rhesus macaques from mucosal challenge with pathogenic simian/human immunodeficiency virus (SHIV) [59,60]. In one case, the challenge was administered orally to neonates [59]; in the other, the challenge was administered vaginally to adult female macaques [60]. Thus, high levels of systemic IgG antibodies can protect some mucosal surfaces from pathogenic challenge. This finding implies that IgG from the peripheral circulation can access mucosal secretions [61].

While the protection in these studies was attributed mainly to neutralization, HIV-specific IgG antibodies may also mediate antibody-directed cell-mediated cytotoxicity (ADCC) through interaction with NK cell Fc receptors. In one study, women with ADCC in cervicovaginal fluids had lower genital HIV viral loads than women with ADCC in serum only [62]. HIV-specific ADCC has also been identified in saliva [63]. Polyclonal or polymeric antibodies specific for HIV envelope may also mediate surface agglutination of viral particles, blocking virus entry via a mechanism distinct from classic neutralization [64*].

The issue of “protective” mucosal antibodies in high-risk cohorts has been controversial [5]. Several groups have reported HIV-specific IgA in plasma or secretions from HEPS individuals [65-71]; these antibodies have been described as neutralizing [72,73] and inhibiting transcytosis across an epithelial monolayer [70,74], although they were unable to block transfer of virus from DC to susceptible target cells [75]. Other studies have failed to detect such antibodies in HEPS cohorts [61,76,77], and a recent study of rhesus macaques repeatedly exposed to low-dose rectal SIV challenge found no evidence for SIV-specific adaptive responses, either humoral or cell-mediated [78*].

Mucosal antibodies in chronic infection

In chronically infected individuals, HIV-specific IgG is readily detected in secretions, yet HIV-specific IgA is detected infrequently and at lower levels than IgG [61,79,80]. Analysis of antibody-secreting cells (ASC) from blood revealed a similar trend: gp160-specific IgG-producing ASC were more abundant than IgA-producing ASC in the same individuals [81]. One detailed study compared the Ig heavy chain gene repertoire of intestinal Ig-secreting cells from HIV-infected and control subjects [82]. Subtle decreases in IgA-producing plasma cells were noted in colon and duodenum of HIV-positive subjects as compared to controls; however, the overall V(H) repertoire of mucosal plasma cells was relatively unperturbed [82]. In another study, the relative proportions of total IgA, G and M-secreting plasma cells were similar in duodenal samples from HIV-positive and healthy individuals [83]. However, the total number of duodenal ASC was greater in HIV-infected subjects; this was also true for IgA and IgG1 secreting cells. The density of lamina propria ASC was highest in patients off therapy or taking nucleoside analogs alone, and was normalized in patients on HAART [83]. These findings are consistent with a recent report describing normalization of B cell populations in blood following HAART [84].

Does HIV infection perturb class switching recombination (CSR)? Such effects could be mediated indirectly by depleting CD4+ “helper” T-cells, or directly through the action of HIV gene products on B cell signaling. One report suggested that HIV Nef penetrates B cells, perturbing CD154 and cytokine signaling and blocking CSR [85]. However, it has also been reported that HIV gp120 can bind B cell mannose C-type lectin receptors, stimulating T-cell independent class switching [86]. Additional work will be required to demonstrate the relevance of these findings to in vivo class switching and mucosal antibody production.

The Female Reproductive Tract

HIV-specific T-cells have been identified in cervical mucosa of women with chronic HIV infection [45,48,87-90], cervicovaginal mucosa of SIV-infected macaques [37,91,92], and cervical cytobrush from HEPS women [93]. In chronically infected individuals, HIV-specific cervical T-cells included MHC class I- and class II-restricted CTL [45]. As demonstrated by redirected lysis and HIV-specific 51Cr release assays, CTL exist throughout the female reproductive tract (FRT), including endo- and ectocervix, vaginal mucosa, uterine endometrium and fallopian tubes [87,94,95]. However, the immunological properties of the FRT change dramatically in response to hormonal fluctuations through the menstrual cycle [96-101]. Notably, CTL activity is specifically suppressed in uterine endometrium during the post-ovulatory phase, presumably to prevent immune rejection of the conceptus [94]. It has been speculated that this temporary suppression of CTL function might provide a window of opportunity for HIV infection and dissemination [102].

The FRT is also equipped with a variety of physical barriers and innate defenses (for review, see [103,104]). Physical defenses include low vaginal pH, multi-layered vaginal epithelium, local flora and a mucous layer. Secretory leukocyte protease inhibitor (SLPI) [105,106], and lactoferrin, a milk protein, are found in a variety of secretions and exhibit anti-HIV activity in vitro [107,108]. The chemokine RANTES [109,110] and several defensin family members [111,112] are also found in the FRT.

Immune defenses in the male reproductive tract, and their potential role in HIV infection and transmission, have been much less studied than those of the FRT. However, HIV/SIV-specific CTL have been identified in semen [113-115]. Renewed attention has focused on the male reproductive tract with the identification of a factor, termed Semen-derived Enhancer of Virus Infection (SEVI), that enhances in vitro infectivity of HIV by several orders of magnitude [116**,117].

Microbicides: the balance between mucosal protection and inflammation

A variety of agents have been tested for the ability to block HIV entry at mucosal surfaces [118*,119*]. Microbicides may act by several mechanisms: by directly inactivating virus particles; by serving as a physical barrier; by enhancing or restoring local bacterial flora; by interfering with virus adsorption, fusion or entry; or by blocking virus replication inside the host cell. One of the most daunting challenges in microbicide development is the identification of compounds that perform these functions without altering the structural integrity of the mucosal epithelium, facilitating HIV entry into target cells, or promoting local inflammation in a way that increases, rather than decreases, the likelihood of HIV transmission.

Several promising microbicide candidates have failed to demonstrate efficacy in clinical trials. Nonoxynol-9 (N-9), a nonionic surfactant, increased HIV incidence in one trial and was found to have a variety of cytotoxic and pro-inflammatory effects [120-122]. Clinical trials of cellulose sulphate (Ushercel) were prematurely halted when results suggested a trend towards increased transmission frequency in women receiving the compound [123]. Given these failures, there is now an urgent need to adopt a broader range of preclinical testing methods to facilitate early identification of compounds with cytotoxic or pro-inflammatory effects [124-126].

Preparations with specific anti-HIV properties, including entry inhibitors [127] and neutralizing antibodies [128], have shown promising microbicide activity in nonhuman primate studies. A variety of antiretroviral compounds and monoclonal antibodies specific for viral or cellular proteins already exist, some of which may hold promise for development as topical microbicides [118*]. In addition, combination preparations incorporating both HIV-specific as well as nonspecific agents, perhaps alongside mucosally delivered vaccines, may be tested in the future.


Given the recent failures of highly publicized vaccine and microbicide trials, there is renewed interest in exploring novel vaccine strategies and further elucidating the role of mucosal immunity in HIV transmission [129**]. Future studies should be directed towards the following questions: (a) What innate and/or adaptive responses constitute “protective” immunity against HIV infection and/or disease progression? (b) How can mucosal responses be harnessed to develop better HIV vaccines and microbicides? (c) How can advances in fundamental mucosal immunology inform the design of HIV vaccines, microbicides and therapeutics? Addressing these questions will require a heightened awareness within the HIV research community of developments in the field of basic mucosal immunology, and increased exchanges of information between the two disciplines.


The author is supported by grants from the National Institutes of Health (NIH/NIAID R01 AI-057020), the California HIV/AIDS Research Program (CHRP, grant CH05-D-606), and the Pendleton Charitable Trust.


*1. Pabst R, Russell MW, Brandtzaeg P. Tissue distribution of lymphocytes and plasma cells and the role of the gut. Trends Immunol. 2008
[A review of the mucosal immune system, including the official terminology adopted by the Society for Mucosal Immunology in 2007.] [PubMed]
2. MacDonald TT. The gut is still the largest lymphoid organ in the body. Mucosal Immunology. 2008 in press.
3. Silvestri G, Paiardini M, Pandrea I, Lederman MM, Sodora DL. Understanding the benign nature of SIV infection in natural hosts. J Clin Invest. 2007;117:3148–3154. [PMC free article] [PubMed]
4. Deeks SG, Walker BD. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity. 2007;27:406–416. [PubMed]
5. Shacklett BL. Understanding the “lucky few”: the conundrum of HIV-exposed, seronegative individuals. Curr HIV/AIDS Rep. 2006;3:26–31. [PubMed]
6. Bjersing JL, Telemo E, Dahlgren U, Hanson LA. Loss of ileal IgA+ plasma cells and of CD4+ lymphocytes in ileal Peyer's patches of vitamin A deficient rats. Clin Exp Immunol. 2002;130:404–408. [PubMed]
7. Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY. Retinoic acid imprints gut-homing specificity on T cells. Immunity. 2004;21:527–538. [PubMed]
8. Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosemblatt M, Von Andrian UH. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature. 2003;424:88–93. [PubMed]
9. Johansson-Lindbom B, Svensson M, Wurbel MA, Malissen B, Marquez G, Agace W. Selective generation of gut tropic T cells in gut-associated lymphoid tissue (GALT): requirement for GALT dendritic cells and adjuvant. J Exp Med. 2003;198:963–969. [PMC free article] [PubMed]
10. Mora JR, Iwata M, Eksteen B, Song SY, Junt T, Senman B, Otipoby KL, Yokota A, Takeuchi H, Ricciardi-Castagnoli P, et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science. 2006;314:1157–1160. [PubMed]
11. Johansson-Lindbom B, Svensson M, Pabst O, Palmqvist C, Marquez G, Forster R, Agace WW. Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing. J Exp Med. 2005;202:1063–1073. [PMC free article] [PubMed]
12. Mora JR, Von Andrian UH. Differentiation and homing of IgA-secreting cells. Mucosal Immunology. 2008;1:96–109. [PubMed]
**13. Arthos J, Cicala C, Martinelli E, Macleod K, Van Ryk D, Wei D, Xiao Z, Veenstra TD, Conrad TP, Lempicki RA, et al. HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol. 2008;9:301–309. [PubMed]
[This paper described a novel mechanism by which HIV-1 envelope induces signal transduction and upregulation of adhesion molecules in mucosal-homing T cells, potentially enhancing cell-to-cell spread of HIV infection.]
14. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007;204:1757–1764. [PMC free article] [PubMed]
**15. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007;317:256–260. [PubMed]
[This study identified retinoic acid as a key mediator of the balance between induction of pro-inflammatory (Th17) and tolerogenic (Treg) CD4 T-cell subsets.]
16. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24:179–189. [PubMed]
*17. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126:1121–1133. [PubMed]
[This study identified the orphan transcription factor RORγt as a key orchestrator of Th17 differentiation, analogous to the role of FoxP3 in Treg differentiation.]
**18. Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008;452:773–776. [PMC free article] [PubMed]
[This paper linked a defect in IL-17 production and Th17 differentiation to the pathogenesis of Job's syndrome, a disease characterized by severe, recurrent bacterial infections.]
19. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–1141. [PMC free article] [PubMed]
*20. Favre D, Lederer S, Kanwar B, Ma ZM, Proll S, Kasakow Z, Miller CJ, Katze M, McCune JM. Primary SIV infection causes rapid loss of the balance between TH17 and T regulatory cell populations in pathogenic infection of non-human primates.. In: Stevenson M, Mellors JW, editors. 15th Conference on Retroviruses and Opportunistic Infections; Boston, MA. February 3-6; 2008. Abstract 117LB.
[One of several recent conference abstracts dealing with the Treg/Th17 balance in SIV infection, this abstract contrasted pathogenic SIV infection of pigtailed macaques to nonpathogenic infection of African green monkeys.]
*21. Cervasi B, Brenchley JM, Paiardini M, Gordon MA, Asher A, Frank I, Else J, Douek DC, Silvestri G. Preferential loss of TH17 CD4 cells in the gastrointestinal tract of HIV-infected individuals but not SIV-infected sooty mangabeys.. In: Stevenson M, Mellors JW, editors. 15th Conference on Retroviruses and Opportunistic Infections; Boston, MA. February 3-6; 2008. Abstract 115.
[One of several recent conference abstracts dealing with the Treg/Th17 balance in SIV infection.]
*22. Cecchinato V, Trindade C, Heraud JM, Laurence A, Brenchley JM, Tryniszewska E, Venzon D, Douek DC, O'Shea J, Franchini G. Preferential loss of TH17 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques.. In: Stevenson M, Mellors JW, editors. 15th Conference on Retroviruses and Opportunistic Infections; Boston, MA. February 3−6; 2008. Abstract 116.
[One of several recent conference abstracts dealing with the Treg/Th17 balance in SIV infection.]
**23. Raffatellu M, Santos RL, Verhoeven DE, George MD, Wilson RP, Winter SE, Godinez I, Sankaran S, Paixao TA, Gordon MA, et al. Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nat Med. 2008;14:421–428. [PMC free article] [PubMed]
[This study demonstrated that SIV infection results in depletion of Th17 cells in ileal mucosa of rhesus macaques, impairing mucosal barrier function and facilitating S. typhimurium dissemination.]
24. Brenchley JM, Price DA, Douek DC. HIV disease: fallout from a mucosal catastrophe? Nat Immunol. 2006;7:235–239. [PubMed]
25. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12:1365–1371. [PubMed]
*26. Chougnet CA, Shearer GM. Regulatory T cells (Treg) and HIV/AIDS: summary of the September 7−8, 2006 workshop. AIDS Res Hum Retroviruses. 2007;23:945–952. [PubMed]
[This paper summarizes findings presented at a recent workshop on the role of Treg in HIV/SIV infection.]
27. Epple HJ, Loddenkemper C, Kunkel D, Troger H, Maul J, Moos V, Berg E, Ullrich R, Schulzke JD, Stein H, et al. Mucosal but not peripheral FOXP3+ regulatory T cells are highly increased in untreated HIV infection and normalize after suppressive HAART. Blood. 2006;108:3072–3078. [PubMed]
28. Andersson J, Boasso A, Nilsson J, Zhang R, Shire NJ, Lindback S, Shearer GM, Chougnet CA. The prevalence of regulatory T cells in lymphoid tissue is correlated with viral load in HIV-infected patients. J Immunol. 2005;174:3143–3147. [PubMed]
29. Estes JD, Li Q, Reynolds MR, Wietgrefe S, Duan L, Schacker T, Picker LJ, Watkins DI, Lifson JD, Reilly C, et al. Premature induction of an immunosuppressive regulatory T cell response during acute simian immunodeficiency virus infection. J Infect Dis. 2006;193:703–712. [PubMed]
30. Nilsson J, Boasso A, Velilla PA, Zhang R, Vaccari M, Franchini G, Shearer GM, Andersson J, Chougnet C. HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS. Blood. 2006;108:3808–3817. [PubMed]
31. Chase AJ, Sedaghat AR, German JR, Gama L, Zink MC, Clements JE, Siliciano RF. Severe depletion of CD4+ CD25+ regulatory T cells from the intestinal lamina propria but not peripheral blood or lymph nodes during acute simian immunodeficiency virus infection. J Virol. 2007;81:12748–12757. [PMC free article] [PubMed]
*32. Boasso A, Vaccari M, Hryniewicz A, Fuchs D, Nacsa J, Cecchinato V, Andersson J, Franchini G, Shearer GM, Chougnet C. Regulatory T-cell markers, indoleamine 2,3-dioxygenase, and virus levels in spleen and gut during progressive simian immunodeficiency virus infection. J Virol. 2007;81:11593–11603. [PMC free article] [PubMed]
[This study found a correlation between regulatory T-cell markers and viral load in plasma and tissues of SIV-infected rhesus macaques.]
33. Haase AT. Perils at mucosal front lines for HIV and SIV and their hosts. Nat Rev Immunol. 2005;5:783–792. [PubMed]
34. Veazey R, DeMaria M, Chalifoux L, Shvetz D, Pauley D, Knight H, Rosenzweig M, Johnson R, Desrosiers R, Lackner A. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science. 1998;280:427–431. [PubMed]
35. Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M, Roederer M. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature. 2005;434:1093–1097. [PubMed]
36. Li Q, Duan L, Estes JD, Ma ZM, Rourke T, Wang Y, Reilly C, Carlis J, Miller CJ, Haase AT. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature. 2005;434:1148–1152. [PubMed]
37. Reynolds MR, Rakasz E, Skinner PJ, White C, Abel K, Ma ZM, Compton L, Napoe G, Wilson N, Miller CJ, et al. CD8+ T-lymphocyte response to major immunodominant epitopes after vaginal exposure to simian immunodeficiency virus: too late and too little. J Virol. 2005;79:9228–9235. [PMC free article] [PubMed]
38. Quigley MF, Abel K, Zuber B, Miller CJ, Sandberg JK, Shacklett BL. Perforin expression in the gastrointestinal mucosa is limited to acute simian immunodeficiency virus infection. J Virol. 2006;80:3083–3087. [PMC free article] [PubMed]
39. Mela CM, Steel A, Lindsay J, Gazzard BG, Gotch FM, Goodier MR. Depletion of natural killer cells in the colonic lamina propria of viraemic HIV-1-infected individuals. AIDS. 2007;21:2177–2182. [PubMed]
40. Nilssen DE, Muller F, Oktedalen O, Froland SS, Fausa O, Halstensen TS, Brandtzaeg P. Intraepithelial gamma/delta T cells in duodenal mucosa are related to the immune state and survival time in AIDS. J Virol. 1996;70:3545–3550. [PMC free article] [PubMed]
41. Lehner T, Mitchell E, Bergmeier L, Singh M, Spallek R, Cranage M, Hall G, Dennis M, Villinger F, Wang Y. The role of gammadelta T cells in generating antiviral factors and beta-chemokines in protection against mucosal simian immunodeficiency virus infection. Eur J Immunol. 2000;30:2245–2256. [PubMed]
*42. Kosub DA, Lehrman G, Milush JM, Zhou D, Chacko E, Leone A, Gordon S, Silvestri G, Else JG, Keiser P, et al. Gamma/Delta T-cell functional responses differ after pathogenic human immunodeficiency virus and nonpathogenic simian immunodeficiency virus infections. J Virol. 2008;82:1155–1165. [PMC free article] [PubMed]
[One of the few studies to address the role of γδ T-cells in HIV/SIV infection, this study focused primarily on peripheral blood.]
43. Veazey RS, Gauduin MC, Mansfield KG, Tham IC, Altman JD, Lifson JD, Lackner AA, Johnson RP. Emergence and kinetics of simian immunodeficiency virus-specific CD8(+) T cells in the intestines of macaques during primary infection. J Virol. 2001;75:10515–10519. [PMC free article] [PubMed]
44. Shacklett BL, Beadle TJ, Pacheco PA, Grendell JH, Haslett PA, King AS, Ogg GS, Basuk PM, Nixon DF. Characterization of HIV-1-specific cytotoxic T lymphocytes expressing the mucosal lymphocyte integrin CD103 in rectal and duodenal lymphoid tissue of HIV-1-infected subjects. Virology. 2000;270:317–327. [PubMed]
45. Musey L, Hu Y, Eckert L, Christensen M, Karchmer T, McElrath MJ. HIV-1 induces cytotoxic T lymphocytes in the cervix of infected women. J Exp Med. 1997;185:293–303. [PMC free article] [PubMed]
46. Couedel-Courteille A, Le Grand R, Tulliez M, Guillet J, Venet A. Direct ex vivo simian immunodeficiency virus (SIV)-specific cytotoxic activity detected from small intestine intraepithelial lymphocytes of SIV-infected macaques at an advanced stage of infection. J Virol. 1997;71:1052–1057. [PMC free article] [PubMed]
47. Schmitz JE, Veazey RS, Kuroda MJ, Levy DB, Seth A, Mansfield KG, Nickerson CE, Lifton MA, Alvarez X, Lackner AA, et al. Simian immunodeficiency virus (SIV)-specific cytotoxic T lymphocytes in gastrointestinal tissues of chronically SIV-infected rhesus monkeys. Blood. 2001;98:3757–3761. [PubMed]
48. Musey L, Ding Y, Cao J, Lee J, Galloway C, Yuen A, Jerome KR, McElrath MJ. Ontogeny and specificity of mucosal and blood human immunodeficiency virus-1 specific CD8+ cytotoxic T lymphocytes. J. Virol. 2003;77:291–300. [PMC free article] [PubMed]
49. Ibarrondo FJ, Anton PA, Fuerst M, Ng HL, Wong JT, Matud J, Elliott J, Shih R, Hausner MA, Price C, et al. Parallel human immunodeficiency virus type 1-specific CD8+ T-lymphocyte responses in blood and mucosa during chronic infection. J Virol. 2005;79:4289–4297. [PMC free article] [PubMed]
50. Critchfield JW, Lemongello D, Young DH, Morris M, Schreiber M, Autret B, Garcia JC, Asmuth D, Pollard RB, Shacklett BL. Functional profile of HIV-specific T cells in rectal mucosa.. In: Stevenson M, Mellors JW, editors. 14th Conference on Retroviruses and Opportunistic Infections; Los Angeles, CA. February 25−28; 2007. Abstract 440.
51. Masopust D, Vezys V, Wherry EJ, Barber DL, Ahmed R. Cutting edge: gut microenvironment promotes differentiation of a unique memory CD8 T cell population. J Immunol. 2006;176:2079–2083. [PubMed]
52. Hayday A, Theodoridis E, Ramsburg E, Shires J. Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat Immunol. 2001;2:997–1003. [PubMed]
53. Shacklett BL, Cox CA, Sandberg JK, Jacobson MA, Stollman NH, Nixon DF. Trafficking of HIV-1-specific CD8+ T-cells to gut-associated lymphoid tissue (GALT) during chronic infection. J. Virol. 2003;77:5621–5631. [PMC free article] [PubMed]
54. Shacklett BL, Cox CA, Quigley MF, Kreis C, Stollman NH, Jacobson MA, Andersson J, Sandberg JK, Nixon DF. Abundant expression of granzyme A, but not perforin, in granules of CD8+ T cells in GALT: implications for immune control of HIV-1 infection. J Immunol. 2004;173:641–648. [PubMed]
*55. Critchfield JW, Lemongello D, Walker DH, Garcia JC, Asmuth DM, Pollard RB, Shacklett BL. Multifunctional HIVgag Specific CD8+ T-cell Responses in Rectal Mucosa and PBMC During Chronic HIV-1 Infection. J Virol. 2007
[This study found higher magnitude HIVgag-specific CD8+ T-cell responses in rectal mucosa as compared to PBMC of individuals with chronic HIV infection and not on antiretroviral therapy.] [PMC free article] [PubMed]
*56. Critchfield JW, Young DH, Hayes TL, Braun J, Garcia JC, Pollard RB, Shacklett BL. Functionality of rectal HIV-1-specific CD8+ T-cells during chronic infection correlates with clinical status.. In: Barouch DH, Mascola JR, McElrath MJ, editors. Keystone Symposium, HIV Vaccines: Progress and Prospects (X7); Banff, Alberta. March 27-April 1; 2008. Abstract 352.
[A detailed analysis of HIV-specific mucosal CD8+ T-cells using simultaneous assessment of four cytokines and a marker for degranulation. This study found significant associations between the magnitude and polyfunctionality of rectal HIV-specific T-cell responses, viral load and CD4 count.]
*57. Brenchley JM, Knox KS, Asher AI, Price DA, Kohli LM, Gostick E, Hill BJ, Hage CA, Brahmi Z, Khoruts A, et al. High frequencies of polyfunctional HIV-specific T cells are associated with preservation of mucosal CD4 T cells in bronchoalveolar lavage. Mucosal Immunology. 2008;1:49–58. [PMC free article] [PubMed]
[This study found strong, polyfunctional HIV-specific T cell responses in bronchoalveolar lavage, but not terminal ileum of HIV-infected subjects.]
*58. Ferre AL, Critchfield JW, Hunt PW, Young DH, Garcia JC, Yee HF, Pollard RB, Deeks SG, Shacklett BL. Polyfunctional T-cells in the rectal mucosa of HIV controllers.. In: Barouch DH, Mascola JR, McElrath MJ, editors. Keystone Symposium, HIV Vaccines: Progress and Prospects (X7); Banff, Alberta. March 27-April 1; 2008. Abstract 143.
[This abstract reported identification of strong, polyfunctional HIV-specific T-cell responses in rectal mucosa of “elite controllers”.]
59. Baba TW, Liska V, Hofmann-Lehmann R, Vlasak J, Xu W, Ayehunie S, Cavacini LA, Posner MR, Katinger H, Stiegler G, et al. Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat Med. 2000;6:200–206. [PubMed]
60. Mascola JR, Stiegler G, VanCott TC, Katinger H, Carpenter CB, Hanson CE, Beary H, Hayes D, Frankel SS, Birx DL, et al. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat Med. 2000;6:207–210. [PubMed]
61. Mestecky J. Humoral immune responses to the human immunodeficiency virus type-1 (HIV-1) in the genital tract compared to other mucosal sites. J Reprod Immunol. 2006;72:1–17. [PubMed]
62. Nag P, Kim J, Sapiega V, Landay AL, Bremer JW, Mestecky J, Reichelderfer P, Kovacs A, Cohn J, Weiser B, et al. Women with cervicovaginal antibody-dependent cell-mediated cytotoxicity have lower genital HIV-1 RNA loads. J Infect Dis. 2004;190:1970–1978. [PMC free article] [PubMed]
63. Kim JS, Nag P, Landay AL, Alves M, Cohn MH, Bremer JW, Baum LL. Saliva can mediate HIV-1-specific antibody-dependent cell-mediated cytotoxicity. FEMS Immunol Med Microbiol. 2006;48:267–273. [PubMed]
*64. Chomont N, Hocini H, Gody JC, Bouhlal H, Becquart P, Krief-Bouillet C, Kazatchkine M, Belec L. Neutralizing monoclonal antibodies to human immunodeficiency virus type 1 do not inhibit viral transcytosis through mucosal epithelial cells. Virology. 2008;370:246–254. [PubMed]
[This study demonstrated that the best-characterized neutralizing monoclonal antibodies to HIV are unable to block transcytosis through an epithelial monolayer in vitro; however, results also suggested that certain polyclonal or polymeric (i.e., S-IgA) antibodies may block HIV attachment by agglutination of virus particles, a process distinct from classic neutralization.]
65. Beyrer C, Artenstein AW, Rugpao S, Stephens H, VanCott TC, Robb ML, Rinkaew M, Birx DL, Khamboonruang C, Zimmerman PA, et al. Epidemiologic and biologic characterization of a cohort of human immunodeficiency virus type 1 highly exposed, persistently seronegative female sex workers in northern Thailand. Chiang Mai HEPS Working Group. J Infect Dis. 1999;179:59–67. [PubMed]
66. Kaul R, Trabattoni D, Bwayo JJ, Arienti D, Zagliani A, Mwangi FM, Kariuki C, Ngugi EN, MacDonald KS, Ball TB, et al. HIV-1-specific mucosal IgA in a cohort of HIV-1-resistant Kenyan sex workers. AIDS. 1999;13:23–29. [PubMed]
67. Kaul R, Plummer F, Clerici M, Bomsel M, Lopalco L, Broliden K. Mucosal IgA in exposed, uninfected subjects: evidence for a role in protection against HIV infection. AIDS. 2001;15:431–432. [PubMed]
68. Mazzoli S, Lopalco L, Salvi A, Trabattoni D, Lo Caputo S, Semplici F, Biasin M, Bl C, Cosma A, Pastori C, et al. Human immunodeficiency virus (HIV)-specific IgA and HIV neutralizing activity in the serum of exposed seronegative partners of HIV- seropositive persons. J Infect Dis. 1999;180:871–875. [PubMed]
69. Mazzoli S, Trabattoni D, Lo Caputo S, Piconi S, Ble C, Meacci F, Ruzzante S, Salvi A, Semplici F, Longhi R, et al. HIV-specific mucosal and cellular immunity in HIV-seronegative partners of HIV-seropositive individuals. Nat Med. 1997;3:1250–1257. [PubMed]
70. Devito C, Broliden K, Kaul R, Svensson L, Johansen K, Kiama P, Kimani J, Lopalco L, Piconi S, Bwayo JJ, et al. Mucosal and plasma IgA from HIV-1-exposed uninfected individuals inhibit HIV-1 transcytosis across human epithelial cells. J Immunol. 2000;165:5170–5176. [PubMed]
71. Devito C, Hinkula J, Kaul R, Lopalco L, Bwayo JJ, Plummer F, Clerici M, Broliden K. Mucosal and plasma IgA from HIV-exposed seronegative individuals neutralize a primary HIV-1 isolate. AIDS. 2000;14:1917–1920. [PubMed]
72. Hirbod T, Kaul R, Reichard C, Kimani J, Ngugi E, Bwayo JJ, Nagelkerke N, Hasselrot K, Li B, Moses S, et al. HIV-neutralizing immunoglobulin A and HIV-specific proliferation are independently associated with reduced HIV acquisition in Kenyan sex workers. AIDS. 2008;22:727–735. [PubMed]
73. Hirbod T, Reichard C, Hasselrot K, Soderlund J, Kimani J, Bwayo JJ, Plummer F, Kaul R, Broliden K. HIV-1 neutralizing activity is correlated with increased levels of chemokines in saliva of HIV-1-exposed uninfected individuals. Curr HIV Res. 2008;6:28–33. [PubMed]
74. Belec L, Ghys PD, Hocini H, Nkengasong JN, Tranchot-Diallo J, Diallo MO, Ettiegne-Traore V, Maurice C, Becquart P, Matta M, et al. Cervicovaginal secretory antibodies to human immunodeficiency virus type 1 (HIV-1) that block viral transcytosis through tight epithelial barriers in highly exposed HIV-1-seronegative African women. J Infect Dis. 2001;184:1412–1422. [PubMed]
75. Soderlund J, Hirbod T, Smed-Sorensen A, Johansson U, Kimani J, Plummer F, Spetz AL, Andersson J, Kaul R, Broliden K. Plasma and mucosal fluid from HIV type 1-infected patients but not from HIV type 1-exposed uninfected subjects prevent HIV type 1-exposed DC from infecting other target cells. AIDS Res Hum Retroviruses. 2007;23:101–106. [PubMed]
76. Skurnick JH, Palumbo P, De Vico A, Shacklett BL, Valentine FT, Merges M, Kamin-Lewis R, Mestecky J, Denny T, Lloyd J, et al. Correlates of non-transmission in United States women at high risk of HIV-1 transmission through sexual exposure. Journal of Infectious Diseases. 2002;185:428–438. [PMC free article] [PubMed]
77. Dorrell L, Hessell AJ, Wang M, Whittle H, Sabally S, Rowland-Jones S, Burton DR, Parren PW. Absence of specific mucosal antibody responses in HIV-exposed uninfected sex workers from the Gambia. AIDS. 2000;14:1117–1122. [PubMed]
*78. Letvin NL, Rao SS, Dang V, Buzby AP, Korioth-Schmitz B, Dombagoda D, Parvani JG, Clarke RH, Bar L, Carlson KR, et al. No evidence for consistent virus-specific immunity in simian immunodeficiency virus-exposed, uninfected rhesus monkeys. J Virol. 2007;81:12368–12374. [PMC free article] [PubMed]
[This study presented an animal model to elucidate potential correlates of protection in HEPS individuals. Rhesus macaques were exposed to repeated low-dose atraumatic rectal challenge with SIVmac. The macaques that remained uninfected did not show evidence of SIV-specific mucosal antibodies or HIV-specific T-cell responses.]
79. Schneider T, Zippel T, Schmidt W, Pauli G, Heise W, Wahnschaffe U, Riecken EO, Zeitz M, Ullrich R. Abnormal predominance of IgG in HIV-specific antibodies produced by short-term cultured duodenal biopsy specimens from HIV-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;16:333–339. [PubMed]
80. Janoff EN, Scamurra RW, Sanneman TC, Eidman K, Thurn JR. Human immunodeficiency virus type 1 and mucosal humoral defense. J Infect Dis. 1999;179(Suppl 3):S475–479. [PubMed]
81. Mestecky J, Jackson S, Moldoveanu Z, Nesbit LR, Kulhavy R, Prince SJ, Sabbaj S, Mulligan MJ, Goepfert PA. Paucity of antigen-specific IgA responses in sera and external secretions of HIV-type 1-infected individuals. AIDS Res Hum Retroviruses. 2004;20:972–988. [PubMed]
82. Scamurra RW, Nelson DB, Lin XM, Miller DJ, Silverman GJ, Kappel T, Thurn JR, Lorenz E, Kulkarni-Narla A, Janoff EN. Mucosal plasma cell repertoire during HIV-1 infection. J Immunol. 2002;169:4008–4016. [PubMed]
83. Nilssen DE, Oktedalen O, Brandtzaeg P. Intestinal B cell hyperactivity in AIDS is controlled by highly active antiretroviral therapy. Gut. 2004;53:487–493. [PMC free article] [PubMed]
84. Moir S, Malaspina A, Ho J, Wang W, Dipoto AC, O'Shea MA, Roby G, Mican JM, Kottilil S, Chun TW, et al. Normalization of B cell counts and subpopulations after antiretroviral therapy in chronic HIV disease. J Infect Dis. 2008;197:572–579. [PubMed]
85. Qiao X, He B, Chiu A, Knowles DM, Chadburn A, Cerutti A. Human immunodeficiency virus 1 Nef suppresses CD40-dependent immunoglobulin class switching in bystander B cells. Nat Immunol. 2006;7:302–310. [PubMed]
86. He B, Qiao X, Klasse PJ, Chiu A, Chadburn A, Knowles DM, Moore JP, Cerutti A. HIV-1 envelope triggers polyclonal Ig class switch recombination through a CD40-independent mechanism involving BAFF and C-type lectin receptors. J Immunol. 2006;176:3931–3941. [PubMed]
87. White HD, Musey LK, Andrews MM, Yeaman GR, DeMars LR, Manganiello PD, Howell AL, Wira CR, Green WR, McElrath MJ. Human immunodeficiency virus-specific and CD3-redirected cytotoxic T lymphocyte activity in the human female reproductive tract: lack of correlation between mucosa and peripheral blood. J Infect Dis. 2001;183:977–983. [PubMed]
88. Passmore J-A. Mucosal assessment of T cell magnitude and specificity during HIV infection. In: Corey L, Esparza J, editors. AIDS Vaccine 2007 August 20−23. Seattle, WA: 2007.
89. Kaul R, Thottingal P, Kimani J, Kiama P, Waigwa CW, Bwayo JJ, Plummer FA, Rowland-Jones SL. Quantitative ex vivo analysis of functional virus-specific CD8 T lymphocytes in the blood and genital tract of HIV-infected women. AIDS. 2003;17:1139–1144. [PubMed]
90. Shacklett BL, Cu-Uvin S, Beadle TJ, Pace CA, Fast NM, Donahue SM, Caliendo AM, Flanigan TP, Carpenter CC, Nixon DF. Quantification of HIV-1-specific T-cell responses at the mucosal cervicovaginal surface. AIDS. 2000;14:1911–1915. [PubMed]
91. Lohman BL, Miller CJ, McChesney MB. Antiviral cytotoxic T lymphocytes in vaginal mucosa of simian immunodeficiency virus-infected rhesus macaques. J Immunol. 1995;155:5855–5860. [PMC free article] [PubMed]
92. Stevceva L, Kelsall B, Nacsa J, Moniuszko M, Hel Z, Tryniszewska E, Franchini G. Cervicovaginal lamina propria lymphocytes: phenotypic characterization and their importance in cytotoxic T-lymphocyte responses to simian immunodeficiency virus SIVmac251. J Virol. 2002;76:9–18. [PMC free article] [PubMed]
93. Kaul R, Plummer FA, Kimani J, Dong T, Kiama P, Rostron T, Njagi E, MacDonald KS, Bwayo JJ, McMichael AJ, et al. HIV-1-Specific Mucosal CD8+ Lymphocyte Responses in the Cervix of HIV-1- Resistant Prostitutes in Nairobi. J Immunol. 2000;164:1602–1611. [PubMed]
94. White HD, Crassi KM, Givan AL, Stern JE, Gonzalez JL, Memoli VA, Green WR, Wira CR. CD3+ CD8+ CTL activity within the human female reproductive tract: influence of stage of the menstrual cycle and menopause. J Immunol. 1997;158:3017–3027. [PubMed]
95. White HD, Yeaman GR, Givan AL, Wira CR. Mucosal immunity in the human female reproductive tract: cytotoxic T lymphocyte function in the cervix and vagina of premenopausal and postmenopausal women. Am J Reprod Immunol. 1997;37:30–38. [PubMed]
96. Lu FX, Ma Z, Rourke T, Srinivasan S, McChesney M, Miller CJ. Immunoglobulin concentrations and antigen-specific antibody levels in cervicovaginal lavages of rhesus macaques are influenced by the stage of the menstrual cycle. Infect Immun. 1999;67:6321–6328. [PMC free article] [PubMed]
97. Yeaman GR, Guyre PM, Fanger MW, Collins JE, White HD, Rathbun W, Orndorff KA, Gonzalez J, Stern JE, Wira CR. Unique CD8+ T cell-rich lymphoid aggregates in human uterine endometrium. J Leukoc Biol. 1997;61:427–435. [PubMed]
98. Wira CR, Rossoll RM. Oestradiol regulation of antigen presentation by uterine stromal cells: role of transforming growth factor-beta production by epithelial cells in mediating antigen-presenting cell function. Immunology. 2003;109:398–406. [PubMed]
99. Sentman CL, Meadows SK, Wira CR, Eriksson M. Recruitment of uterine NK cells: induction of CXC chemokine ligands 10 and 11 in human endometrium by estradiol and progesterone. J Immunol. 2004;173:6760–6766. [PubMed]
100. Sentman CL, Wira CR, Eriksson M. NK cell function in the human female reproductive tract. Am J Reprod Immunol. 2007;57:108–115. [PubMed]
101. Poonia B, Walter L, Dufour J, Harrison R, Marx PA, Veazey RS. Cyclic changes in the vaginal epithelium of normal rhesus macaques. J Endocrinol. 2006;190:829–835. [PubMed]
102. Yeaman GR, White HD, Howell A, Prabhala R, Wira CR. The mucosal immune system in the human female reproductive tract: potential insights into the heterosexual transmission of HIV. AIDS Res Hum Retroviruses. 1998;14(Suppl 1):S57–62. [PubMed]
103. Wira CR, Fahey JV, Sentman CL, Pioli PA, Shen L. Innate and adaptive immunity in female genital tract: cellular responses and interactions. Immunol Rev. 2005;206:306–335. [PubMed]
104. Coombs RW, Reichelderfer PS, Landay AL. Recent observations on HIV type-1 infection in the genital tract of men and women. AIDS. 2003;17:455–480. [PubMed]
105. McNeely TB, Dealy M, Dripps DJ, Orenstein JM, Eisenberg SP, Wahl SM. Secretory leukocyte protease inhibitor: a human saliva protein exhibiting anti-human immunodeficiency virus 1 activity in vitro. J Clin Invest. 1995;96:456–464. [PMC free article] [PubMed]
106. Fahey JV, Wira CR. Effect of menstrual status on antibacterial activity and secretory leukocyte protease inhibitor production by human uterine epithelial cells in culture. J Infect Dis. 2002;185:1606–1613. [PubMed]
107. Ma G, Greenwell-Wild T, Lei K, Jin W, Swisher J, Hardegen N, Wild CT, Wahl SM. Secretory leukocyte protease inhibitor binds to annexin II, a cofactor for macrophage HIV-1 infection. J Exp Med. 2004;200:1337–1346. [PMC free article] [PubMed]
108. Berkhout B, Floris R, Recio I, Visser S. The antiviral activity of the milk protein lactoferrin against the human immunodeficiency virus type 1. Biometals. 2004;17:291–294. [PubMed]
109. Iqbal SM, Ball TB, Kimani J, Kiama P, Thottingal P, Embree JE, Fowke KR, Plummer FA. Elevated T cell counts and RANTES expression in the genital mucosa of HIV-1-resistant Kenyan commercial sex workers. J Infect Dis. 2005;192:728–738. [PubMed]
110. Hirbod T, Nilsson J, Andersson S, Uberti-Foppa C, Ferrari D, Manghi M, Andersson J, Lopalco L, Broliden K. Upregulation of interferon-alpha and RANTES in the cervix of HIV-1-seronegative women with high-risk behavior. J Acquir Immune Defic Syndr. 2006;43:137–143. [PubMed]
111. Cole AM. Innate host defense of human vaginal and cervical mucosae. Curr Top Microbiol Immunol. 2006;306:199–230. [PubMed]
112. Venkataraman N, Cole AL, Svoboda P, Pohl J, Cole AM. Cationic polypeptides are required for anti-HIV-1 activity of human vaginal fluid. J Immunol. 2005;175:7560–7567. [PubMed]
113. Quayle AJ, Coston WM, Trocha AK, Kalams SA, Mayer KH, Anderson DJ. Detection of HIV-1-specific CTLs in the semen of HIV-infected individuals. J Immunol. 1998;161:4406–4410. [PubMed]
114. Huang XL, Fan Z, Gupta P, Rinaldo CR., Jr. Activation of HIV type 1 specific cytotoxic T lymphocytes from semen by HIV type 1 antigen-presenting dendritic cells and IL-12. AIDS Res Hum Retroviruses. 2006;22:93–98. [PubMed]
115. Letvin NL, Schmitz JE, Jordan HL, Seth A, Hirsch VM, Reimann KA, Kuroda MJ. Cytotoxic T lymphocytes specific for the simian immunodeficiency virus. Immunol Rev. 1999;170:127–134. [PubMed]
**116. Munch J, Rucker E, Standker L, Adermann K, Goffinet C, Schindler M, Wildum S, Chinnadurai R, Rajan D, Specht A, et al. Semen-derived amyloid fibrils drastically enhance HIV infection. Cell. 2007;131:1059–1071. [PubMed]
[This paper described a novel semen-associated factor, termed “SEVI”, derived from prostatic acid phosphatase. This factor enhances HIV infectivity in vitro by several orders of magnitude.]
117. Roan NR, Greene WC. A seminal finding for understanding HIV transmission. Cell. 2007;131:1044–1046. [PubMed]
*118. Balzarini J, Van Damme L. Microbicide drug candidates to prevent HIV infection. Lancet. 2007;369:787–797. [PubMed]
[This paper provides a detailed review of potential HIV microbicides, including drugs with highly specific anti-HIV activity.]
*119. van de Wijgert JH, Shattock RJ. Vaginal microbicides: moving ahead after an unexpected setback. AIDS. 2007;21:2369–2376. [PubMed]
[This paper reviews the results of HIV microbicide trials to date, including a discussion of potential explanations for trial results in the direction of harm.]
120. Fichorova RN, Tucker LD, Anderson DJ. The molecular basis of nonoxynol-9-induced vaginal inflammation and its possible relevance to human immunodeficiency virus type 1 transmission. J Infect Dis. 2001;184:418–428. [PubMed]
121. Hillier SL, Moench T, Shattock R, Black R, Reichelderfer P, Veronese F. In vitro and in vivo: the story of nonoxynol 9. J Acquir Immune Defic Syndr. 2005;39:1–8. [PubMed]
122. Van Damme L, Ramjee G, Alary M, Vuylsteke B, Chandeying V, Rees H, Sirivongrangson P, Mukenge-Tshibaka L, Ettiegne-Traore V, Uaheowitchai C, et al. Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial. Lancet. 2002;360:971–977. [PubMed]
123. Honey K. Microbicide trial screeches to a halt. J Clin Invest. 2007;117:1116. [PMC free article] [PubMed]
124. Lard-Whiteford SL, Matecka D, O'Rear JJ, Yuen IS, Litterst C, Reichelderfer P. Recommendations for the nonclinical development of topical microbicides for prevention of HIV transmission: an update. J Acquir Immune Defic Syndr. 2004;36:541–552. [PubMed]
125. Shattock RJ, Doms RW. AIDS models: microbicides could learn from vaccines. Nat Med. 2002;8:425. [PubMed]
126. Moench T, Mehrazar K, Cone R, Blumenthal P. Sensitive methods to detect epithelial disruption: tests for microhemorrhage in cervicovaginal lavages. J Acquir Immune Defic Syndr. 2004;37(Suppl 3):S194–200. [PubMed]
127. Veazey RS, Klasse PJ, Schader SM, Hu Q, Ketas TJ, Lu M, Marx PA, Dufour J, Colonno RJ, Shattock RJ, et al. Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion. Nature. 2005;438:99–102. [PubMed]
128. Veazey RS, Shattock RJ, Pope M, Kirijan JC, Jones J, Hu Q, Ketas T, Marx PA, Klasse PJ, Burton DR, et al. Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nat Med. 2003;9:343–346. [PubMed]
**129. Shattock RJ, Haynes BF, Pulendran B, Flores J, Esparza J. Improving Defences at the Portal of HIV Entry: Mucosal and Innate Immunity. PLoS Med. 2008;5:e81. [PMC free article] [PubMed]
[This article summarized a workshop held in June, 2007 in Durham, NC with the goal of identifying key scientific priorities for future studies of innate and mucosal immunity in the context of HIV infection.]