Sexual transmission of HIV: infectiousness and prevention

Introduction HIV can be transmitted through contaminated blood and blood products; from a mother to her offspring during pregnancy, childbirth or breast feeding; or through sexual contact. Sexual transmission remains by far the predominant mode of transmission 1. Vertical and blood borne transmission of HIV are highly predictable, and very efficient modes. The recipient of a unit of contaminated blood nearly always becomes infected, whereas only about 0.3% of people pierced with large bore needles seroconvert 2. This difference in efficiency most probably reflects the dissimilar concentrations of viruses inoculated. Vertical transmission leads to infection in about 25% of newborns 3. Sexual transmission of HIV, however, appears to be considerably less efficient and highly variable 4,5. To develop effective prevention strategies, a better understanding of the factors affecting transmission of HIV is required. The probability of transmission of HIV is a function of infectiousness of the index case, the mode of the sexual contact and the susceptibility of the person exposed to the virus. Whereas non-transmission of HIV in steady partnerships is found frequently, some individuals have transmitted the virus to the majority of their heterosexual partners 6. Potential explanations for this variability in sexual transmission of HIV include biological differences in infectiousness, susceptibility or both, or differences in sexual behaviors. Susceptibility to HIV infection has recently been reviewed by Padian in this Journal 7. The purpose of this article is to review factors that contribute to HIV infectiousness. Epidemiological studies on infectiousness of HIV Disease stage and infectiousness Epidemiological studies have documented the risks of HIV transmission by all routes 8. Longitudinal partner studies have improved our understanding of the sexual transmission of HIV and factors influencing the infectiousness of HIV infected individuals 9-17. In general, HIV transmission by any route is more likely when the index case is found to have a greater degree of immunosuppression (as manifested by reduced CD4 count or more advanced stage of disease, Table 1) 9,11,13,15,16,18,19. When analyzed in partner studies, the transmission rate is approximately two to three times greater from infected males to females than from infected females to males 14,20. In HIV epidemic areas in Africa, however, the rate of transmission is more evenly distributed between the sexes 21. Hayes et al. 22 calculated the cofactor effect of genital ulcer diseases to be approximately five times higher for female-to-male than for male-to-female transmission. Thus, in countries with high sexually transmitted disease (STD) prevalence, the higher cofactor effect for female-to-male transmission could counterbalance the higher risk of transmission of male-to-female sex in the absence of STDs.Table. 1: Summary of published partner studies evaluating factors associated with infectiousness.Sexual behavior and infectiousness Differences in sexual acts and other behavioral factors may also predict the efficiency of transmission of HIV. The risk of vaginal intercourse appears to be considerably less than insertive anal intercourse 11,19. Whereas fellatio has been considered a much lower risk behavior 8,18 recent studies with macaques 23 as well as reports of homosexual men with primary infection 24 indicate that oral transmission may occur. Sexually transmitted diseases and infectiousness The relationship between classical STDs and the transmission of HIV has been appreciated for a long time 25. In a number of studies it has been shown that the prevalence and incidence of HIV is considerably greater in patients who present to STD clinics with genital ulcers and mucosal inflammatory diseases 22,26-32 and in patients with a history of STD 11,33,34. HIV acquisition appears to be increased in women with inflammation of the cervix 35. However, STDs might facilitate HIV transmission by increasing the genital shedding (infectivity) of HIV. In a study in Haiti, higher transmission risks were documented for patients with a diagnosis of syphilis 17. In addition, concomitant transmission of HIV with STDs might play an important role. In a study of primary HIV infection, Kinloch de Loes et al. 36 reported genital ulcers in 13 out of 25 sexually infected primary infection cases examined. Regardless of whether STDs increase infectiousness of HIV or increase susceptibility, their importance in HIV transmission has been confirmed by Grosskurth and coworkers 37. These investigators demonstrated a 42% reduction in incident cases of HIV in several African villages that implemented an aggressive STD treatment program. Use and pitfalls of mathematical models to describe HIV transmission Several authors have used mathematical models to describe sexual transmission of STDs and HIV infection. In most partner studies the models do not address the question of whether the risk of transmission is a function of the number of sexual acts. Based on a number of pivotal studies by Anderson and May 38 several authors have previously suggested that the risk of transmission is a function of the number of partners rather than of the number of sexual contacts 13,18,34,39,40. Recent work by Downs et al. 41 supports this concept, indicating that, in a given partnership, transmission of HIV is most likely to occur during the first few sexual contacts, after which the risk of transmission per contact becomes considerably smaller. In general, the risk of transmission per contact (in the range of 0.1-0.5%) is considerably smaller in studies of steady partnerships 14 than in studies of single sexual contacts with prostitutes 33,42. Therefore, studies of steady partnerships are clearly subject to a selection bias favoring circumstances with low risk of transmission. The studies select for seronegative partners who may have natural as well as acquired resistance to HIV infection and may also select for seropositive cases with low infectiousness. It has been suggested that the uninfected partner may develop an HIV- or a partner-specific (e.g. anti-HLA) immune response during the first few sexual contacts with the infected partner which reduces the risk of transmission during subsequent sexual exposures 43. Several lines of evidence suggest the possibility of acquired immunity 44-46 and additional longitudinal studies are needed to resolve these issues. Data obtained from studies of artificial insemination illustrate further the possible risk of a single exposure to HIV contaminated semen. In a retrospective study of five fertility clinics, where 199 women were inseminated with unprocessed semen from their HIV infected donor, seven (3.5%) were found to be HIV-positive 47. This result further suggests that longitudinal partner studies may underestimate the per-contact transmission probability of HIV from men-to-women. Jacquez and coworkers 48 have developed a model of the HIV epidemic which supports an increased HIV transmission during primary infection. This model assumes that recently infected patients continue to engage in high risk sexual behavior, and that biological factors (e.g. high viral load) render such patients particularly contagious. The model predicts per-contact infectivity during primary HIV infection to be 100 to 1000 times higher than during the asymptomatic period of the disease. However the model could be flawed, since it assumes a constant per-contact transmission probability which, as discussed above, may not be appropriate. In addition, the model does not consider changes in susceptibility of seronegative partners to infection nor is it based on empirical findings. Mechanism of mucosal transmission The exact source of the virus from the infected partner, the mucosal route of the virus during transmission, and the target cell in the mucosa of the recipient are still not known. From cases of HIV transmission by artificial insemination, it is clear that semen can transmit the virus 47,49. This is also supported by the finding of a protective effect occurring with coitus interruptus 14. The cellular fraction of semen contains spermatozoa, immature germ cells, leukocytes (lymphocyte, granulocytes and macrophages), and epithelial cells. HIV can be detected in lymphocytes/monocytes and cell free seminal plasma. Interestingly, vasectomy does not result in a reduction of shedding of HIV in semen as measured by HIV-RNA levels, indicating that most cell-free HIV in seminal plasma arises distal to the vas deferens 50. HIV has also been found to be associated with sperm cells by electron microscopy and in situ polymerase chain reaction (PCR) 51,52, but these findings are highly controversial 53-55. However, the fact that more than 1400 artificial insemination procedures with processed sperm from men with HIV failed to result in transmission of HIV indicates that the motile sperm fraction from semen is not likely to transmit the virus (A. Semprini, personal communication and 56). The processing used by Semprini and others separates motile spermatozoa from contaminating leucocytes by density-gradient centrifugation and swim-up technique. Whether HIV is predominantly transmitted as a cell-free virus or in a cell-associated form is not known. In the macaque model, vaginal infection with simian immunodeficiency virus (SIV) is established more efficiently using cell-free virus 57. Information gained from in vitro cell culture experiments with human cervical epithelia and HIV indicate a potential mechanism for cell-associated infection 58,59. In this model, the HIV infected monocyte adheres to the monolayer and viral particles are internalized by pinocytosis into the epithelial cell. In addition, Furuta et al. 60 have demonstrated that vaginal epithelial cells can be infected by HIV via a CD4 independent mechanism similar to that described for neuroglial cells. This mechanism involves initial interaction of the HIV-1 envelope gp120 with a cell-surface glycosphingolipid which can be blocked by antibodies raised against gp120. Whether dendritic cells in the subepithelial tissue can serve as a direct target for HIV or are infected after a passage of the virus through the epithelial cell layer is not known. The relative contribution made by cell-free and cell-associated HIV in sexual transmission remains under investigation. Information on the biology of female-to-male transmission is limited. HIV can be detected in endocervical swab specimens, cervicovaginal lavage samples, and CD4 positive cells 61,62 but little is known about potential target cells in the male genital tract 63. Miller et al. 64 have been able to infect male macaque after placing cell-free virus on the penile urethra. The laboratory assessment of infectiousness of HIV In general, infectious transmission of a pathogen is concentration and pathogen dependent. HIV infectiousness must reflect the effects of the level of HIV present in the inoculum and its phenotype. There are now several lines of evidence supporting the idea that HIV infectiousness is a function of virus concentration. Patients with high blood viral load were more likely to transmit the disease to recipients of blood 65, their sexual partners 16,66,67, and their offspring 3. Conversely, antiviral therapy taken by an HIV infected mother late in pregnancy significantly reduces transmission to her offspring 68. However, better understanding of sexual transmission of HIV requires evaluation of the effects of viral concentration in genital secretions. Given the transmissibility of HIV through semen and the high risk of male-to-female transmission, further analysis of the effects of semen is clearly essential. However, only recently have detailed large scale studies been undertaken. The lack of probably reflects the relative of semen and also the in HIV in semen samples, which have now been improved Several procedures for and HIV have been and these include and for cell-associated and cell-free HIV-RNA culture is and and of infectious HIV from seminal cells has been highly variable and also variable when from time of infectious HIV from seminal plasma has this may be seminal plasma is to cells in culture in the of under that this however, of HIV from seminal plasma are low These suggest that seminal leucocytes may be for the infectiousness of a finding which with gained from the macaque model where mucosal infection is more by cell-free than cell-associated virus 57. Table Summary of published studies evaluating factors associated with increased shedding of HIV in the genital recent studies have the concentration of HIV by HIV-RNA in the seminal plasma The variability of the HIV-RNA detected has also been with et al. semen from patients under and found only variability of less than However, et al. reported a much greater variability in patients with blood viral In general, HIV-RNA in semen with HIV-RNA in blood plasma. However, the degree of this is in the range of indicating that factors other than the viral load in blood the level in semen HIV-RNA found in semen may also in from in the genital HIV-RNA concentration in seminal plasma is highly associated with a positive HIV culture from seminal cells HIV-RNA only the concentration of cell-free virus in semen. assessment of in seminal cells by has been reported In a study of semen taken from detected in semen from only of study However, the level of with the of infectious virus from seminal cells by culture Whereas between infectious and the between and culture supports the of as a for infectious virus The concentration of HIV in the genital tract can be to sexual and transmission of HIV. Whereas some investigators have HIV or detected in cervicovaginal only recently have large scale studies been and studies using have also been These studies are by the variability in since some investigators endocervical or vaginal swab and others cervicovaginal factors associated with increased of HIV in genital factors Whereas some of the HIV present in the genital tract is HIV concentration in the genital tract is also a function of the concentration of HIV in blood is in the genital this through blood and genital or as a result of similar most studies that HIV-RNA concentration in blood and genital found a but between the two that increase the viral in blood as or could increase shedding of HIV in the genital advanced stage of might also the or of the genital The rate of of infectious HIV in seminal cells is increased in patients with more advanced of the disease Whereas smaller studies failed to an between HIV in seminal plasma and stage of disease or CD4 count studies have shown a but of HIV concentration in semen with of these also with CD4 in semen and is with CD4 and HIV-RNA are also more detected in cervical of women with a more advanced stage of disease low CD4 count and to have effects that have been particularly well in of in the genital tract has been documented in women with and in women high oral or of primary infection The concentration of HIV in semen in primary infection has only been to a et al. the concentration of HIV-RNA in semen and blood in three with primary HIV disease Whereas in with disease the blood viral as very HIV in seminal plasma were not the range of found for a of with HIV infection. et al. found similar in a study of a of These studies failed to a biological to the models discussed which a to increased risk of transmission during primary infection. antibodies are from genital in primary infection, however, the infectious potential of these may be greater for any given concentration of virus in semen. factors The of HIV in the genital tract does not reflect the blood viral and several findings the of the genital the between the concentration of HIV in genital and blood is in most studies with an between and the variability of HIV-RNA in semen time may be higher than the variability of its in blood analysis has some in HIV from the genital tract as to HIV from blood It likely that increase of HIV in the genital In vitro work supports this and coworkers demonstrated that infection HIV in vitro increased concentration of tissue and in men with have been obtained when HIV is exposed to and coworkers found that cervicovaginal from approximately of women of HIV in vitro The as cervical and tract probably work through of the inflammation can also be to increase HIV by of inflammatory cells into the genital secretions. The most of inflammation in the genital tract is other of inflammation and factors in STDs may increase the susceptibility to HIV by mucosal or by increasing the number of cells that are to HIV infection. However, an or additional is that STDs render HIV-positive individuals more contagious. Several studies increased of HIV in the male genital tract of patients with STDs The study to this relationship in an STD in where HIV-positive men with were to an HIV infected In this an increased of HIV, which with the therapy and reduction in genital tract the HIV concentration in semen for STDs effect on the blood viral from this also demonstrated that patients with genital ulcers also a significantly higher concentration of HIV in an mechanism as additional or inflammatory by which ulcers might transmission of HIV studies have been on HIV shedding in the genital tract in the from the of demonstrated that cervical shedding of HIV-RNA increased in women with genital ulcers but not with cervical of STDs the rate of of from the of has shown that of from endocervical swab from women an STD in is increased significantly with but not with cervical or infection However, studies on women who have indicate that the cervix is not for the shedding of HIV in the genital tract and et al. found increased cervical and vaginal shedding of in women with and coworkers demonstrated increased of CD4 positive cells in cervical swab from patients with STDs Whereas these are to suggest increased susceptibility to HIV, these cells could also be to increase infectiousness. factors of viral factors have been suggested to play a in the infectiousness of these include envelope for transmission, factors that the and of the and resistance to antiviral with macaques using and have demonstrated that vaginal transmission of cell free virus requires envelope and vaginal and infection of in infection with a viral with envelope whereas vaginal to infection with a envelope in with primary infection also for sexual transmission of virus et al. transmission of a of HIV in a study of sexual transmission of HIV in five In of the five the transmitted could be found in the semen of the index and in three of these cases the transmitted were found in the semen but not in the These findings suggest that some viral factors transmission, that some the mucosal or level the transmission of but not viral that to sexual transmission of HIV have been HIV form in as a result of in the envelope These are associated with more advanced HIV authors suggested that the of HIV are transmitted whereas others have not been able to a transmission of In some patients differences in of and in semen and blood have been reported However, of on a positive selection by the culture and are always present as well and found and in semen and evidence for a semen in the Thus, transmission of it is likely to occur in the recipient and the viral envelope is likely to play an important in this In the model, et al. a transmission of three envelope vaginal but not or also can be used to HIV than of all HIV in the result from the African The HIV epidemic in the and has from of HIV whereas the epidemic in has from of in homosexual and in heterosexual contacts found in a study in behavioral and factors have been used to these it also possible that some are transmitted with greater efficiency than from men to partners To this et al. the of primary of of HIV in dendritic reported more efficient of than However, other investigators have not been able to these findings and it clear that as source of dendritic cells and culture may recently has the biology of been to the concentrations of HIV in the semen and blood of study in are significantly higher than of patients in the for CD4 count This could to the rate of in or it might reflect the effects of factors with that are more in In addition, viruses of are not from blood or semen of patients with HIV of the stage of the disease. of a predominant of might transmission. Miller and coworkers recently demonstrated that the of the viral predicts the transmission of for mucosal transmission in the model susceptibility to antiviral might the infectiousness of HIV. of an HIV that is to has been reported a study on reduced in vitro infectivity of virus has been the of these for transmission has not been the infectiousness of HIV of HIV on infected and only a fraction of HIV infected people are of their prevention on who are However, the most effective to diseases when are not is to infectiousness This requires the of as HIV infected as possible a but of to the patients and and biological can be to the risk of transmission behavior in HIV infected of are to shedding of HIV, with the that some level patients with HIV be less contagious. and biological must be and to viral shedding must not patients with HIV to that are not therapy can be to the transmission of HIV. of transmission have been when is only to late in pregnancy Patients therapy have shown reduced transmission of HIV to their partners There has been an increase in the number of studies that that treatment reduces of HIV in genital and the concentration of HIV in semen In most patients the reduction of HIV in semen that in and in patients HIV-RNA can be detected in seminal plasma after therapy is Conversely, in some patients HIV in genital during and resistance to has been demonstrated in HIV in semen and genital resistance could with by concentrations in genital secretions. To is on concentration in semen. are for and In these the concentration of in seminal plasma higher than in blood plasma and from semen et al. reported that and were much lower in semen than in blood but still in vitro to and in semen with the concentration of HIV in semen are in et Patients to be about the of treatment reduction of genital shedding of HIV. infectiousness does not lack of transmission and more not antiviral treatment does result in reduced infectiousness. In to be effective on a reduced infectiousness must be with sex and reported that of HIV infected that therapy the for sex Whereas et al. reported similar and were to a between and a of sex In the of to in the for therapy is and to be used to HIV transmission. to HIV concentration include treatment of and genital tract that increase shedding of HIV. Whereas the of STDs in countries has been recent studies a prevalence of STDs in patients with HIV in and the (e.g. that increase genital tract viral or shedding be be antiviral therapy to shedding of HIV in the that HIV, to be used to infectiousness and and of immune factors that shedding in the genital that that to HIV transmission can be The risk of HIV transmission on several factors that infectiousness and susceptibility of these factors are highly of infectiousness can be during of disease, during that increase the blood viral as well as during associated with inflammation in the genital susceptibility to infection appears to be higher during the first few sexual contacts, the risk of transmission obtained from partner studies may underestimate the risk associated with a single sexual contact. HIV in genital appears to be a to an degree of infectiousness. relationship between HIV infectiousness and The infectiousness of a during the of HIV infection is by the In this it is that infectiousness during primary infection and during of disease The level of infectiousness during the asymptomatic of the infection is by two of a sexually transmitted disease The susceptibility of steady partners is by to the partner can occur during time when infectiousness in the index case the relative degree of resistance in the partner appears to be to HIV infection and does not and a protective HIV immune response in the relationship and do not infected the infectiousness of the index case of a genital inflammatory or as a result of immunodeficiency becomes infected during the first sexual HIV prevention have been on However, biological suggest that infectiousness of HIV-positive may also be an efficient and effective improved understanding of HIV infectiousness is for this to be to for This work supported by and the and and by a of the