the role of sexually transmitted diseases in hiv transmission

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REVIEWSTable 2 | Types of sexually transmitted infectionsCharacteristicsAetiological agentsSystemic infections without mucosal disease HIV, hepatitis B, cytomegalovirusGenital ulcers Haemophilus ducreyi, herpes simplex virus 1 and 2,Treponema pallidumMucosal inflammationNeisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalisChanges in epithelial cellsHuman papillomavirusMUCOSAL NEOPLASMUsually carcinomas, such ascervical carcinomas, that areassociated with certain typesof HIV.COHORT STUDIESStudies in which subsets of adefined population areidentified.CHANCROID LESIONSSingle or multiple painful,necrotizing ulcers at the site ofinfection, which are frequentlyaccompanied by painful swellingand suppuration of regionallymph nodes.ADJUSTED-ODDS RATIOThe estimated odds ratio afterany confounding factors havebeen taken into account.the CCR5 receptor and are highly resistant to HIVinfection 48 ;conversely, higher expression of CCR5co-receptors might be associated with an increase insusceptibility to HIV infection 49 .Some differences in susceptibility could be relatedto gender. There is evidence that women mightbecome infected with more HIV variants than men orinfants 50 .Different viral variants were found in 20 of32 recently HIV-infected women compared with 0of 10 recently infected men. These viral variants werefound before seroconversion, indicating that they didnot develop after immune selective pressure, and werenot co-infections from multiple partners 51 .It is stillunknown what causes this tendency towards infectionwith multiple viral variants in women 51 .The proposed role that female sexual hormonesmight have in infectiousness has already been discussed.Other studies have documented the role of femalesexual hormones in susceptibility to HIV infection.Progesterone therapy increases susceptibility to simianimmunodeficiency virus (SIV) in macaques — possiblyowing to a thinning of the vaginal epithelium 52 .Treatment of ovariectomized macaques with subcutaneousoestrogen protected the animals from vaginalSIV challenge 52 , leading the authors to conclude thattopical vaginal oestrogen might be useful in reducingHIV susceptibility in post-menopausal women orwomen receiving only progesterone.STDs and HIV transmissionSTDs can be divided into four categories: those that produceno mucosal signs or symptoms; those that producevarying degrees of mucosal inflammation; those thatproduce genital ulcers; and those that cause epithelialcellchanges and/or MUCOSAL NEOPLASM (TABLE 2). Theinteraction between these ‘traditional’ STD pathogensand HIV has attracted a great deal of attention, andhas been referred to as ‘epidemiological synergy’ 34 .HIV can influence the prevalence or manifestationsof other STDs, and other STDs can have an impacton HIV transmission. There is compelling evidencefor the effects of STDs on the transmission ofHIV 34–36 .However, it has been difficult to determinewhether an individual STD increases the infectiousnessof HIV, the susceptibility of individuals to HIVor (more than likely) to both HIV and an STD, or todetermine which STD has the greatest effect on HIVtransmission.A remarkable number of epidemiological studieshave been undertaken to link STDs and HIV 5,34–36 .Intheir review, Fleming and Wasserheit 34 examinedSTDs and HIV transmission in the context of studiesof biological plausibility, COHORT STUDIES and clinicaltrials. The greatest attention has been directed towardscohort studies that focus on HIV acquisition and‘attributable risk’ 34 .In such studies, the HIV status of astudy subject is determined together with the history orrecord of detection of an STD. By comparing STDs insubjects with and without HIV infection, the contributionof STDs can be estimated. The problems with thisapproach include the limitations of the use of historicaldata as a proxy for an STD; the limitations of theSTD assays that are available; and an inability to detectco-transmission of HIV and STD pathogens 34–36 .To examine the role of STDs further, we will attemptto ‘deconstruct’ the effects of STDs on the infectiousnessand susceptibility of HIV.STDs and infectiousnessThe effects of an STD on the infectiousness of HIVcould be measured prospectively, but such work has notbeen undertaken so far. Rather, several indirectapproaches have been used.Effects on HIV shedding. It is possible to examine theinfluence of STD pathogens on the excretion of HIV ingenital secretions. On the basis that the concentrationof HIV in genital secretions determines the probabilityof transmission, the direct measurement of HIV seemsto be a reasonable proxy, both in men and women.However, there are technical limitations to thisapproach 5,36 , including difficulty sampling the femalegenital tract, contamination of genital secretions withblood and variability between different assays 27 .Additionally, it remains unclear whether HIV is transmittedby infected cells or by cell-free virus.STDs that cause ulcers generally increase shedding(detection) of HIV in the genital tract 34–36,53 .This canoccur by direct shedding of HIV from the ulcerativelesion. HIV has been detected by culture and PCR fromthe exudate of CHANCROID LESIONS 54 .Studies in female sexworkers showed a 3.9 ADJUSTED-ODDS RATIO for sheddingHIV in the presence of a vaginal or cervical ulcer 33 .Thelesions need not be purely infectious in nature to havean effect — ulcerations of the cervix that are associatedwith treatment of intraepithelial lesions were found toincrease HIV levels 55 . GUD can also affect HIV levels insemen by affecting systemic viral loads or increasinglocal inflammation. In a study in Malawi, men withgenital ulcers and non-gonococcal urethritis were foundto shed higher amounts of HIV in semen comparedwith men with urethritis alone 56 .36 | JANUARY 2004 | VOLUME 2 www.nature.com/reviews/micro
REVIEWSHIV RNA(copies ml –1 seminal plasma)200,000150,000100,00050,000UNIVARIATE ANALYSISExamines the effect of onevariable.0All urethritis(n = 74)Gonococcalurethritis(n = 49)Controls(n = 45)Figure 3 | The effects of urethritis on the viral load of HIV in semen. n denotes the numberof patients in each sample. Modified with permission from REF. 66 © (1997) Elsevier ScienceHIV RNA(copies ml –1 seminal plasma)1,000,000100,00010,0001,000T. vaginalis(sole pathogen)As the most common causative agent of GUDworldwide, HSV has an important role in HIV infections57,58 . HIV-1 RNA was detected in ulcer swabs in 25of 26 men with symptomatic HSV-2 infection, and thelevels exceeded 10,000 copies ml –1 of swab sample inmost cases 59 .The levels of HSV shedding correlate withHIV plasma viral levels 60 .Even asymptomatic HSVshedding was found to be associated with increasedHIV shedding 61 .STDs that cause inflammation increase the concentrationof HIV in the urethra, semen 62–66 and cervicalfluid 32,33 .In patients with urethritis, gonorrhoea seemsto have a greater effect on the viral load in the genitaltract than chlamydia 67 , as might be predicted by thehigher degree of inflammation that is usually caused bygonorrhoea. However, less purulent STDs, such asTrichomonas-associated urethritis in men, have beenshown to increase semen viral load 62,63 , and this is alsocorrelated with the degree of urethral inflammation.n = 6 n = 18STD patientsNo pathogenidentifiedP = 0.0218n = 9 n = 33T. vaginalis(sole pathogen)No pathogenidentifiedDermatology patientsFigure 4 | The effects of Trichomonas vaginalis infection on the viral load of HIV in semen.n denotes the number of patients in each sample. The mean viral load for each patient group isshown by the thick black bar.Even asymptomatic urethritis has been associated withHIV shedding in semen 64 .As shown in FIGS 3 and 4,gonococcal and Trichomonas urethritis cause a substantialincrease in the concentration of HIV in the semen.A study that examined women from Cote d’Ivoire 33 ,found that GUD, gonorrhoea and chlamydia haveeffects in UNIVARIATE ANALYSIS, whereas trichomonas,syphilis and vaginitis do not.Treatment of STDs reduces the concentration ofHIV in genital secretions 33,66–68 .In HIV-infected womenwith an STD that was successfully treated, the proportionwho had detectable cervicovaginal HIV fell from42% to 21% at a seven-day follow-up visit; whereas inwomen whose STD was not cured and women withoutSTDs, there was no change in the proportion whowere shedding HIV (36% and 17%, respectively) 33 .Inmen who were treated for urethritis, the concentrationsof HIV RNA in the semen fell from an average of1.24 × 10 5 copies ml –1 to 4.12 × 10 4 copies ml –1 at twoweeks 66 .In most cases, treatment of the STD does notreduce the concentrations of HIV RNA to those seen inHIV-infected persons without STDs 67 .Analyses of the blood viral burden in subjects withgenital-tract infections show somewhat conflictingresults. In men, the HIV concentration in the bloodremained unchanged before and after treatment of urethritis66 .However, Anzala et al. reported that HIV bloodlevels rose during gonococcal cervicitis and pelvicinflammatorydisease, and returned to baseline levelsafter treatment 69 .In one study, GUD was associatedwith a higher plasma viral load 56 .The effect of HSVinfection on the viral burden of HIV in blood has beenthe subject of unresolved but important debate aboutthe adjunctive potential of HSV antiviral therapy onthe management of HIV. HIV viral load has beenfound to increase in subjects having a HSV outbreak 18 .In a trial of individuals who are co-infected with HIVand HSV-2, Schacker et al. found that treatment withacyclovir reduced HIV plasma viral loads 60 .Effects on HIV replication. A modest number ofexperiments have been conducted in vitro to examinethe direct effect of various STD pathogens on HIVreplication. Ho et al. found that replication of HIV inmononuclear cells is increased in the presence ofpolymorphonuclear cells (PMNs) and that this effect iseven greater with the addition of C. trachomatis 70 .Another study showed that human herpesvirus-8induces HIV replication 71 . Treponema pallidum (theaetiological agent of syphilis) induces HIV geneexpression and this increased expression correlateswith increased binding of nuclear factor (NF)-κB to thepromoter region of the HIV provirus long-terminalrepeat 72 .Clinical evidence comes from work thatshowed that HSV shedding without clinical ulcers stillincreases cervical HIV levels 61 .Speck et al. have reportedthat the presence of CMV in the genital tract can alsoincrease HIV replication, perhaps through direct viraltransactivation 65 . CMV shedding from the cervix issignificantly associated with HIV shedding in womenwith both CMV and HIV infections 73 .NATURE REVIEWS | MICROBIOLOGY VOLUME 2 | JANUARY 2004 | 37
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