Work

Targeting Trojan Horse leukocytes for HIV prevention

Year: 2009

Type: review

Abstract: Introduction ….is sure design’d, by fraud or force: trust not their presents, nor admit the horse. Virgil, Aeneid Human immunodeficiency virus type 1 (HIV-1), the lymphotropic virus that causes AIDS, has infected more than 60 million people worldwide since its clinical appearance in 1981. Despite intensive prevention efforts, the HIV/AIDS epidemic continues to spread, particularly in developing countries in sub-Saharan Africa, southeast Asia and the Caribbean, as well as the developed world [1]. Although HIV can be transmitted very efficiently parenterally, the advent of routine blood screening prior to transfusion and harm reduction programs for injection drug users, have made this mode of transmission much less common than mucosal transmission. Most new HIV infections are attributable to mucosal transmission: through genital and rectal mucosae in the case of sexual transmission and through oral or gastrointestinal mucosae in the case of mother-to-child transmission [2]. Much has been learned about HIV pathogenesis and infection mechanisms at the molecular level, but the scientific community has yet to develop an effective vaccine or microbicide for HIV prevention. Many unanswered questions remain concerning HIV-1 sexual transmission. In 1983, barely 2 years into the AIDS epidemic, we hypothesized that the agent that was subsequently identified as HIV-1 may be sexually transmitted by infected ‘Trojan Horse’ leukocytes in semen [3]. This hypothesis was based on our knowledge at the time that human semen contains substantial numbers of T lymphocytes and macrophages, which could host a T-cell tropic virus, and the following assumptions: intracellular virus would be better protected than free virus from adverse effects of antiviral factors in the genital environment such as antiviral antibodies likely to be present in genital secretions of the virus-infected transmitter, as well as antimicrobial peptides that play an important role in genital innate immune defense; and virus-infected allogeneic cells could also escape early detection by major histocompatibility complex (MHC)-restricted cytotoxic T cells in a new host. Over the intervening 25+ years, others have also championed this cause [4,5], and convincing evidence has emerged from clinical research as well as in-vitro and animal studies that infected leukocytes indeed play a role in HIV transmission. Yet, most recent research on sexual HIV transmission has focused on cell-free HIV in genital secretions because of the wide availability of HIV RNA quantification assays. Furthermore, the majority of HIV vaccines and microbicides have been designed to block transmission of cell-free virus and have been tested in animal and in-vitro models that use cell-free virus as the only infectious inoculum. As the molecular events underlying cell-associated HIV transmission differ from those underlying cell-free virus transmission, many of the current vaccine and microbicide candidates might not be expected to protect against cell-associated HIV transmission. The failure of several recent vaccine and microbicide clinical trials may be due in part to this oversight. It should be possible to design strategies that block cell-associated HIV transmission as well as cell-free HIV transmission. In this article, we present an overview of research that has been conducted on cell-associated HIV mucosal transmission and recommendations for future research. We focus on sexual HIV transmission, but this review also has relevance for mother-to-child HIV transmission, which may occur through mucosal transmission of cell-associated HIV from maternal genital or mammary gland secretions [6–8]. We review published reports that describe and enumerate HIV-infected cells in genital secretions, and compelling evidence from clinical, animal and in-vitro studies demonstrating that such cells can transmit HIV across genital tract epithelial surfaces; potential molecular mechanisms underlying cell-associated HIV transmission that could be specifically targeted by future HIV prevention strategies; and in-vitro and animal cell-associated HIV transmission models currently used for studies on cell-associated HIV transmission mechanisms and for testing vaccine and microbicide candidates. Using this information as a foundation, we discuss the evidence and probability that various current microbicide and vaccine approaches prevent cell-associated HIV transmission, and suggest additional microbicide and vaccine concepts and experiments that will move this field forward. Putative cellular vectors of HIV mucosal transmission Seminal leukocytes Cell populations The principal in human semen are and blood cells semen from various the the and play an role in semen have been and by and Most of studies that semen from contains on the of the majority of which are substantial numbers of and T cells are also present T cells in This the case in HIV-infected in lymphocytes are in of the of to lymphocytes in semen was 1 that are the most host in semen and a likely principal of cell-associated HIV in human genital secretions, identified by T in in leukocytes in semen from a in blood in of in semen are an genital by more than semen in of and as many as of HIV-infected semen contains of and T cells In the has and the T-cell 2 are in more HIV-infected cells have also been in a from the of and sexual and may also the sexual transmission of HIV important host cells such as and cells have not been in possible that HIV-infected cells from the are in the or and of HIV-infected leukocytes in semen Most studies of HIV in semen have used HIV RNA to numbers of cell-free in only a have used HIV to the or of HIV-infected cells in In the of HIV in semen has from to and the of HIV has from not to in of the studies that HIV RNA and numbers in not HIV in semen have been HIV infection and recent sexually transmitted infection and of of HIV RNA and are in HIV cells can in semen for several and have been to be infectious in on HIV in of HIV-infected in semen has not been this we to a that was used in a on factors HIV in semen from from this of HIV and host cells and T by that only a HIV was present in infected and that only and T cells the infection of this host was of semen cells the in that HIV-1 could be from cells a of have HIV from cells and cell-free the of infectious HIV from cells has been much than that from The HIV from that HIV and numbers are in than in the semen This that much of the cell-free HIV in semen or of factors have been identified in that may antibodies and The could also the of to blood cells used for HIV HIV from semen that the and of HIV-infected leukocytes in semen Although can be in semen from several factors may the and of in genital tract infections and are numbers genital infections not and as HIV infection to and lymphocytes in semen an by studies that HIV transmission by was a in HIV RNA numbers in which following studies have HIV RNA from genital by various Most of studies have only cell-free HIV but because infections and are in that the of HIV-infected cells in semen also to has that HIV RNA and in semen from a recent and have also been of cell-free and cell-associated HIV in semen as well as of and that could HIV in infected cells may be particularly due to In from our semen from million and million T cells human million In their semen was infectious cells of HIV in the and blood such as may play an important role in the HIV HIV infection also have of HIV RNA in and studies that are infectious has HIV in semen of infected of from HIV-infected of infection tested for HIV research to HIV-infected in semen to the of this HIV transmission by The of transmit HIV infection has been for several years HIV and immunodeficiency cells and early and studies evidence that human may HIV or RNA have not been and most recent studies have not HIV infection of from HIV-infected from in semen by of HIV or RNA may be due to of the infected leukocytes or or could that HIV infection of but We HIV in populations from semen of HIV-infected and HIV in and T-cell but not in In the we also the of populations from semen of and that T cells and infectious cells in from the not infectious from that have used from HIV-infected to evidence that are not Over have been from HIV-infected infection of the in of substantial to the that transmit HIV following As detection of HIV in could HIV infection of Furthermore, several have that HIV can to through or This may be as HIV may be by but this could be following as could HIV to host cells in the as well as In a recent from HIV-infected to HIV that HIV-infected cells could HIV to or cells in the genital tract in genital secretions Cell populations studies have host cells in and but have or populations in human and and T cells are but not in secretions from or HIV-infected The of lymphocytes in secretions from due to the effects of in the human in are in secretions of and infections can In to have or on but cells could have and due to this and of HIV-infected leukocytes in genital secretions studies on HIV in secretions have used HIV as an of HIV in secretions has been and and or The of HIV-infected cells in secretions in on a studies have HIV in cells from secretions In HIV on the of HIV RNA and in secretions from in the the of of HIV but not and HIV transmission on HIV in of leukocytes studies on HIV from not cells from cell-free the to of and HIV conducted cell-free from to to has the HIV from cell-free cell-associated of HIV was from of cell-free and of Although of HIV from have not been possible that HIV-infected leukocytes from are by by and less infectious We that HIV-infected genital leukocytes from due to such as and are more infectious than those from in the and are more of cell-associated HIV transmission. a was used to the detection of infectious HIV in genital Although the was was only a numbers and HIV RNA In of more than HIV RNA of infectious HIV in the The that the may of cell-free virus in genital secretions, by or innate immune the potential of cell-associated HIV transmission. HIV cells in genital mucosae HIV from an infectious an environment that contains a of factors from and genital rectal environment not as well but would be expected to many of the As several factors in semen and secretions can cell-free but may not HIV-infected in this environment that have been to cell-associated HIV transmission are that and protect genital mucosal and that to a In an in-vitro lymphocytes and leukocytes to to the of present the of the and and T cells and by in the human the of secretions for several by the of and leukocytes a of to the genital Furthermore, and underlying and are also that infected leukocytes in genital secretions can remain at for several in and in and and are of HIV through genital secretions to the epithelial such as those and are of a epithelial such as those and mucosae of a of epithelial In the epithelial infectious such as HIV or cells the epithelial studies have that HIV-infected T cells and to mucosal epithelial and that their of HIV the epithelial can and epithelial cells may be by epithelial cells to an to an which could be to the through of or by the epithelial or may be across epithelial cells to cells in the We and others have also that and T cells can and epithelial in more infected cells or the HIV-infected epithelial and HIV-infected lymphocytes to the of an epithelial of HIV-infected from semen virus a genital tract epithelial by from the from as well as and in the of the populations that may as HIV cells in genital mucosae are T cells the epithelial can be and cells are and can be infected by HIV virus to cells in The that the epithelial and that into the host cells macrophages, and the from to at the of the an of HIV cells HIV may also cells in the and of HIV cells in the genital are In use of such as the can the genital and rectal in and of macrophages, and cells into the epithelial and secretions numbers of host cells are in and secretions, and in rectal and secretions, due to and in semen and effects of semen on mucosal epithelial cells would be expected to cell-associated HIV transmission. for cell-associated HIV transmission studies The sexual transmission of HIV a for the probability of HIV transmission from 1 in for transmission, 1 in for transmission, and 1 in for transmission on the of HIV from blood of infected HIV-1 that in the majority of of the transmission a virus from an infected for clinical infections This that HIV transmitted a HIV or infected transmission has been in studies of and can an infection in the due to of the mucosal numbers of HIV cells at the infection HIV in semen differ from those in blood and at studies evidence that of cell-free HIV differ from those of cell-associated HIV in semen should be possible to the transmission by a cell-free or an HIV-infected to in and that the of the virus that of HIV in semen cells of the in of and studies of this are to the and factors of cell-associated HIV transmission. evidence that leukocytes can the in by a that that an allogeneic in that for their sexual human This was not in that used and likely by to leukocytes because not As the human a for immune and the allogeneic was in that the leukocytes the mucosal to an immune in but was also in the and could be to to In this from allogeneic HIV-1 infection of T cells from their evidence that allogeneic could protect against cell-associated HIV transmission. studies immunodeficiency virus The animal of cell-associated transmission across and rectal mucosal was the immunodeficiency virus infection a to T cells and causes an immunodeficiency in was of the animal models used to mechanisms of HIV transmission and pathogenesis can be transmitted of infected T cells or cell-free virus or rectal and this was used to the of early microbicide candidates against and rectal transmission of cell-associated The has also been used for vaccine the of developing a vaccine to protect against a T-cell tropic T-cell of vaccines based on virus and virus-infected cells are effective and could be learned from vaccine models about of against cell-free and cell-associated transmission across mucosal models In the that cells could the following in the the cells and the was that HIV-infected human could the in to a HIV infection a for studies on cell-associated HIV transmission. In the cell-associated but not cell-free virus infection due to of cells The of the to the and infection less HIV-infected cells are in human their into the models have been human cells of are cells and populations and are to infection following of cell-free HIV prior or mucosal recent to HIV infection following rectal of cell-free and cell-associated HIV in studies have been to on cell-associated HIV transmission in the and the the only to for cell-associated HIV transmission studies and for testing approaches to block of infected cells and their across a can be infected HIV and but are used for HIV transmission research due to their on HIV transmission in conducted in that cells and of cell-free HIV-1 of infection into the the The most common used for studies on mechanisms of HIV-1 sexual transmission has been the Although most studies on transmission in have used cell-free recent studies have the of cell-associated transmission. early was at of but at the infection was in and in following infectious cells in and RNA was in of and which than of cell-free infection that cells of and T from infected at the of also efficiently transmit HIV in of infection was following cells infected cells in the and studies are because the of virus in the cell-associated on the of as HIV through cell-associated HIV HIV have been in human studies use of that are several of than the and HIV in most studies of HIV-infected cell-associated models would be for testing of microbicide and vaccine candidates for against cell-associated HIV transmission. models epithelial have been used to HIV transmission. HIV from infected cells can of or gastrointestinal epithelial cells through a to cells the cell-associated HIV also across of epithelial cells In of HIV-infected leukocytes much more than cell-free virus in infection of cell-associated HIV was not in a epithelial and was infected cells to the of of human and or and epithelial the relevance of this cell-associated HIV transmission HIV-infected T cells and cells are currently used to microbicides for against cell-associated HIV transmission as the genital epithelial are to of HIV and may be infected free from infected have also been used for studies of cell-associated HIV transmission. In cell-free or cell-associated HIV on the of in and transmission was by HIV in the at time The of cell-associated and cell-free HIV and cell-free virus in transmission of the virus across the In cells from semen to to and the but to to due to their in by We have used transmission and to and human to the of human to the and epithelial cells We have also their of an human human and transmission of human blood to epithelial intracellular and transmission of human blood epithelial transmission in-vitro models are for testing the of microbicides and antibodies and cytotoxic T cells against several mechanisms underlying cell-associated HIV transmission and of infected cells through of infected cells to the of HIV across of infected cells through the and of events underlying cell-associated HIV transmission The HIV transmission hypothesis that HIV-infected in the genital tract or rectal sexual protect and virus to cells or the mucosal to a new host. The studies evidence that HIV-infected leukocytes are present in genital secretions and that can indeed to the mucosal through the and the of this HIV-infected cells from genital secretions may transmit virus across the genital of through at In the the genital epithelial a HIV-infected leukocytes to the of epithelial cells and the epithelial infectious may be by epithelial cells for to host cells the or through the epithelial by to cells in the The of virus from infected leukocytes to cells the through the of an infectious possible that cells are to infected leukocytes by by the infected or by epithelial cells that are by the infected infected leukocytes may through the to cells in the or underlying cell-associated HIV transmission. epithelial cells to host cells in the or HIV through epithelial cells to cells in of HIV from infected to epithelial which virus to or cells through or of of HIV from infected to of infected to cells the of infected to cells in the or and of immune cells from blood across the into the well the of that leukocytes to from the into the has yet to be studies have a role for a of and their in intracellular epithelial In much has been to the role of in and This but may be by and the role of in and to the mechanisms of cell-associated HIV transmission. to the and transmission studies conducted in the early that HIV-infected cells to epithelial cells and the of epithelial which to HIV-infected also to epithelial cells and from the microbicide candidates to have been in and epithelial cells and T cells a of that their to epithelial cells and host cells the The and to a of present on the of and T The of or more of the to in a of such as and has been as the in the of immune cells and the of not but can be by The to this present in in semen and could on leukocytes the in a into an that to and and in cell-associated HIV the of in an for Furthermore, to the availability of its particularly by T and cells the mucosal at the of It has been hypothesized that this in of leukocytes following a The and to play an important role in the of HIV In an that of HIV-infected on an and antibodies across the was by the cells and an of and It was also that the T cells and cells and antibodies HIV transmission peptides from of and from the of have been to block peptides the and block the for many of peptides are by T cells following to the and are as potential to to cells are also for in and an important of We have the of and by epithelial cells in and that may also play a role in of genital to the are in the mucosae and T could play a role in as well as the of lymphocytes at this tract also the which to specifically to present in epithelial in the and has an important role in the of the was that may also play a role in and the on T has a for and the for this that mucosal T cells or cells to remain at the infection may play a role in immune in the case of a lymphotropic virus such as as cells for The T-cell has been in T-cell in the HIV the mucosal of T lymphocytes to the and can the HIV This a of the of which HIV through intracellular The T-cell also on T cells in the and genital tract and recent evidence that T-cell populations are following HIV through the important of in mucosal such as the and to potential and in the and to T cells and the use to to epithelial cells as their and to into the from animal and in-vitro studies suggest that and HIV-infected leukocytes are of in genital or the epithelial would and and T which could as the of HIV infection the host. of transmission in animal and in-vitro models cell-free virus that T and are early leukocytes may be to into the mucosal by a of have been in genital tract secretions are by epithelial cells others are by leukocytes in the The and of the and the for HIV of are and of such as and are of T cells and to of and have been in of immune cells through by genital or in to infection in the epithelial environment In by epithelial cells and leukocytes an infection additional leukocytes to the infection infection of and epithelial cells of the and in to various It likely that cell-associated HIV transmission may also through the and the and of cells the HIV The immune to cells their to the the of and are of and HIV have to HIV transmission on the of a the This of infection very and the virus to a host immune The events of on the of to at the of the The are for and at the of In the case of HIV-1 this on and the of the such as and and to a The that this the type of can the of and the of or the of and the of a through which the virus can be by and of and to the by and and transmission, as by have been identified as a mode of virus transmission for and cells as well as T lymphocytes HIV transmission may also occur and approaches to cell-associated HIV transmission The suggest that microbicides and vaccines should be developed that are effective against cell-associated as well as cell-free are several mechanisms by which this can be and of the microbicide and vaccine candidates and clinical may be effective against this in HIV prevention. a of the studies that have been conducted to microbicide and vaccine candidates in cell-associated HIV transmission assays. It be that this an and that are In the following we based on and which approaches will be effective against various events underlying cell-associated HIV transmission. trials conducted in cell-associated HIV transmission models animal and in-vitro models that can be used for cell-associated HIV transmission research. microbicide candidates have been tested in animal cell-associated virus sexual transmission and mucosal transmission of infected T cells in the in from the in and several microbicide candidates have cell-associated HIV transmission in and the was in the rectal cell-associated HIV transmission The only vaccine was conducted in the vaccines based on virus or following cells but not following cell-free virus HIV transmission microbicides and approaches have also been tested in in-vitro cell-associated HIV transmission of the and of human and the of through In and rectal epithelial which HIV and antibodies to HIV the and a of antibodies microbicides and mechanisms that could be effective at of cell-associated HIV transmission of the could the of infectious cells in genital secretions and block cell-associated HIV transmission. early microbicide in the genital leukocytes in and cell-associated transmission was to be in an that used the most that those in for more likely to infected used the that infected cells and cell-free HIV present in in secretions, but that also an that HIV cells to the genital which can HIV transmission HIV to the that are effective in this such as have not trials but that could be developed in the potential could be in and animal are developed as microbicides to a and in such as This may be effective against cell-free and cell-associated HIV transmission as HIV are and HIV-infected cells may be and by The microbicide in this to be tested in a clinical HIV was may have the more in this are and may be more could important of a agent to develop that a in and and the of semen In to the of the could be to or to prevent HIV can cells in This was in the field the that antibodies in their possible that antibodies against on HIV-infected cells in genital secretions could the of cells through antibodies could be as a of microbicide and a that cells in semen and peptides that block and and of leukocytes to epithelial cells could cell-associated HIV transmission are also important of could also block this cell-associated HIV transmission The of HIV from infected leukocytes cells in the for approaches to HIV are of the The from antibodies to and to of that specifically HIV and in cell-free transmission in that may against HIV or and the that has the of clinical a that was a reduction in HIV transmission in and in a conducted by the in the will be the of microbicide for HIV prevention. are developing that are of and HIV to HIV and to cells could also block of infected leukocytes can or block the infected cells the epithelial or the to epithelial could also block the of cells to of an that immune and and by human epithelial was to prevent mucosal transmission of cell-free by of HIV cells to infection in the could also the of infected cells and cells that cell-associated HIV transmission. approaches to block of infected leukocytes to epithelial intracellular and and cytotoxic T cells and cellular could HIV-infected cells as the genital has also been for against cell-free and cell-associated HIV transmission of type 1 in the which could protect against cell-associated HIV transmission of cell-free was not by this because the also an that more host cells to the studies have that HIV infection can be are or The most has been a of suggest that or effective in and rectal transmission in models that studies have the of and genital tract trials of as well as oral to prevent HIV transmission are currently are also for their role in a agent and a agent Although will only HIV has and are in genital secretions, that could be effective in cell-associated infection of cells in the genital the of intracellular HIV in HIV of could be particularly effective in cell-associated HIV transmission microbicide candidates and mechanisms that could block cell-associated transmission are in microbicide candidates that could prevent cell-associated HIV transmission by genital evidence from clinical, animal and in-vitro studies that infected cells Horse’ may be important vectors of HIV-1 mucosal transmission. This an in the field of HIV and a of questions remain unanswered the of cell-associated HIV transmission cell-free HIV transmission, and factors are cell-associated HIV of infected cells transmit HIV across mucosal and are the cells of cell-associated HIV HIV the time of infected leukocytes in the genital cell-associated HIV transmission are the molecular events underlying cell-associated HIV transmission that can be targeted by studies molecular of in infected have cell-associated and cell-free HIV transmission. studies should be to the and factors cell-associated HIV transmission in and in-vitro models for studies of cell-associated HIV

Source: AIDS

DOI: 10.1097/qad.0b013e32833424c8

Authors: Deborah J Anderson, Joseph A Politch, Adam M Nadolski, Caitlin D Blaskewicz, Jeffrey Pudney, Kenneth H Mayer