Sexually transmitted
diseases enhance HIV transmission: No Longer a Hypothesis
Myron S Cohen
Lancet 1998; 351 (suppl III):5-7
Departments of Medicine, Microbiology, and Immunology,
University of North Carolina at Chapel Hill, NC 27599-7030, USA (M
S Cohen, MD)
Sexual transmission of HIV-1 almost certainly depends on the size of the inoculum of virus, the phenotype of the viral isolate, and the susceptibility of the host.1 HIV-1 can be quantified in semen,2-4 and detected in female genital secretions.5,6 Detection of HIV-1 in genital secretions increases in patients with later stages of disease and in patients with lower CD4 lymphocyte counts;2-6 these factors are likely to reflect higher blood concentrations of HIV-1. High concentrations of HIV-1 can also be detected in the blood and in the semen of patients with primary HIV-1 disease (ref 7 and Connie Celum, University of Washington, Seattle, WA, USA, personal communication), in which epidemiological models suggest accelerated HIV-1 transmission.1 Although the concentration of HIV-1 required for transmission by any route is not known, it has been suggested that high blood plasma HIV-1 concentrations increase the likelihood of sexual transmission,8-10 and the concentration of HIV-1 in blood correlates with the concentration in semen.2,3 Antiviral drugs that reduce the concentration of HIV-1 in these compartments may reduce sexual transmission of HIV-1.8
Sexual acquisition of HIV-1 seems to depend on infection of receptive cells by specific viral quasispecies (figure). Several lines of evidence suggest that mucosal dendritic cells that express both CCR5 and CD4 receptors are the target for HIV-1.11 Accordingly, people who are homozygous for a deletion in the CCR5 receptor have at least partial resistance to HIV-1 infection.12 Infected dendritic cells seem to transport HIV-1 to lymphocytes, where the infection of CD4 cells so characteristic of HIV disease occurs.11
Transmission of HIV-1 through exposure of vaginal endocervical cells to semen. Semen contains syncytia-inducing (SI) and non-syncytia-inducing (NSI) HIV-1 isolates. NSI isolates are preferentially transmitted, most likely through uptake by CD4 and CCR5 receptors expressed on monocytic and dendritic cells.
The HIV-1 envelope defines the cell types that are susceptible to infection in vitro.13-15 Viral isolates that are tropic for macrophages (and fail to form cellular syncytia in vitro) are found in the blood of patients with primary HIV-1 disease, and seem to be more readily transmitted by any route than those isolates that only show tropism for T lymphocytes (and form cellular syncytia in vitro).15 The HIV-1 envelope also helps define different viral types called clades. The idea that clades may differ in efficiency of infectiveness has attracted considerable attention and controversy.16-18
Identification of patients who are exposed to HIV-1 but remain uninfected suggests the possibility of acquired immunity.19 Indeed, some exposed but uninfected individuals have increased amounts of secretory immunoglobulins directed against HIV-1 in genital mucosal secretions,19 and/or increased cytotoxic-T-lymphocyte responses.20
The explosive spread of HIV-1 in areas where classic sexually transmitted diseases (STDs) are epidemic (eg, sub-Saharan Africa, Thailand) has encouraged a remarkable number of studies designed to examine the association between these STDs (urethritis, cervicitis, and genital ulcers) and HIV-1 infection.1,21,22 Wasserheit has called this relation "epidemiological synergy",21 a phrase that emphasises the difficulty in proving that STDs enhance HIV-1 transmission, and in understanding precise biological mechanism(s) responsible for this phenomenon. Classic STDs could facilitate HIV-1 transmission by increasing either the infectiousness of the index case, the susceptibility of the partner, or both.1,21,22
With a model of chlamydia and HIV-1 coinfection, Ho and co-workers23 found that chlamydia increased the replication of HIV-1, perhaps through the generation of reactive oxygen products secreted by granulocytes. More recently, Treponema pallidum lipoproteins have been shown to increase HIV-1 replication.24 STD pathogens could disrupt mucosal tissues, and/or increase the number of cells receptive to HIV-1, and/or the number of receptors expressed per cell. Chlamydial infection causes secretion of cytokines that could be expected to affect either replication of HIV-1 and/or number of receptive cells.25
The effects of STDs on excretion of HIV-1 in genital secretions have been investigated.5,6,26-31 Moss et al27 detected HIV-1 DNA in the urethra more frequently in patients with gonococcal urethritis than in controls or in patients who had been treated. Cohen et al28 studied 86 HIV-1-positive patients with urethritis and observed an eight-fold increase in secretion of HIV-1 RNA in semen compared with a control group. The concentration of HIV-1 RNA in semen fell 2 weeks after appropriate antibiotic therapy to values not significantly different from those of controls. Gonorrhoea and trichomoniasis had the most substantial effect on HIV-1 RNA excretion. Patients with genital ulcers also had increased excretion of HIV-1 RNA in semen,29 perhaps because of changes in local concentrations of cytokines or because these patients had a more advanced stage of disease.
Investigators in Kenya6,30 and the Ivory Coast5 found that HIV-1 DNA was significantly increased in cervicovaginal fluids of patients with STDs. Ghys and co-workers5 noted a significant increase in detection of HIV-1 DNA in cervicovaginal-lavage samples from patients with gonorrhoea, chlamydia, cervicovaginal ulcer, or cervical mucopus. A week after STD treatment, detection of HIV-1 in these secretions decreased from 42% to 21%; changes in detection rate were not observed in women whose STDs were not cured. Mostad et al30 noted a significant increase in detection of HIV-1 in swab samples in women with gonococcal cervicitis and vaginal candidiasis, but not trichomoniasis or chlamydia.6 Increases in detection of HIV-1 DNA were also observed in pregnant women with cervical discharge.
STDs might increase the number of cells receptive to HIV-1. Levine and co-workers31 found increased CD4 cells in genital secretions from women with STDs compared with controls. Spear et al32 have detected cytokines in genital secretions of women with HIV-1 infection that could affect expression of cell-surface receptors and/or replication of HIV-1.
Intervention trials have also established the importance of STDs in HIV-1 transmission. Grosskurth et al33 showed that improved STD treatment in Mwanza, Tanzania, led to a 42% reduction in incident cases of HIV-1; an intervention that also reduced STD prevalence.34 An ongoing trial of mass antibiotic therapy for STDs in Ugandan villages is nearly complete,35 and the effects of such intervention on the transmission of HIV-1 are awaited with great anticipation.
A causal link between HIV-1 transmission and classic STDs has been demonstrated.22,33 How can we use these data to plan HIV-1 prevention? Mathematical models have been developed to predict the impact of different interventions on HIV-1 transmission,36 and prevention choices depend heavily on the prevalence and relative importance of the cofactors examined. In countries where STDs and HIV-1 coincide, treatment of STDs can be expected to reduce transmission of HIV-1 in a cost-effective manner.36,37 Although available data make it difficult to focus on particular STDs, the effects of gonorrhoea on excretion of HIV-1 in semen support the timely treatment of this infection.28 The high prevalence of trichomoniasis in both men and women may also prove to be important for HIV-1 transmission. In addition, rapidly evolving data seem to show that the changes in vaginal flora characterised as bacterial vaginosis may facilitate acquisition of HIV-1.38,39
To reduce HIV-1 transmission in developing countries, priority must be placed on syndromic management of STDs and use of effective antimicrobial drugs.40 Improved ways to detect STDs in symptom-free people, especially women, are also essential. Behavioural messages should continue to encourage health-seeking behaviour and "safer sex" including condom use.40 Development of behavioural messages focused on HIV-1-infected individuals is anticipated, since responsible sexual behaviour in this population is absolutely essential for HIV-1 prevention.
In developed countries, the relative importance of STDs for HIV-1 transmission is more controversial, mainly because of limited data. The prevalence of HIV-1 in patients that present with STDs is considerably higher than in the general population.41 Recently, studies in the USA and UK have found continued incidence of STDs in patients with HIV-1 disease (refs 42, 43, and Myron S Cohen, unpublished data). Detection and treatment of classic STDs must be undertaken in HIV-1-positive patients to reduce their viral infectiousness, and in their partners to reduce susceptibility to infection.
This work was supported by US National Institutes of Health grants and the USAID IMPACT Program. I thank Joe Eron, Gina Dallabetta, and Irving Hoffman for their comments. The figure was prepared by Marcia Hobbs.
1 Royce RA., Seńa A, Cates W, Cohen M. Sexual transmission of HIV-1. N Engl J Med 1997; 336: 1072-78.
2 Vernazza PL, Gilliam B, Dyer JR, et al. Quantification of HIV in semen: correlation with antiviral treatment and immune status. AIDS 1997; 11989-95.
3 Combs RW, Speck CE, Hughes JF, et al. Association between culturable human immunodeficiency virus type 1 (HIV-1) in semen and HIV-1 RNA levels in semen and blood: evidence for compartmentalization of HIV-1 between semen and blood. J Infect Dis 1998; 177: 320-330.
4 Xu C, Politch JA, Tucker L, Mayer KH, Seage GR III, Anderson DJ. Factors associated with increased levels of human immunodeficiency virus type 1 DNA in semen. J Infect Dis 1997; 176: 941-47.
5 Ghys PD, Fransen K, Diallo MO, et al. The associations between cervicovaginal HIV shedding, sexually transmitted diseases and immunosuppression in female sex workers in Abidjan, Côte d'Ivoire. AIDS 1997; 11: F85-93.
6 Mostad SB, Overbaugh J, DeVange DM, et al. Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina. Lancet 1997; 350: 922-27.
7 Dyer J, Gilliam B, Eron JJ, Cohen MS, Fiscus S, Vernazza P. Shedding of HIV in semen during primary infection. AIDS 1997; 11: 543-45.
8 Musicco M, Lazzarin A, Nicolosi A, et al. Antiretroviral treatment of men infected with human immunodeficiency virus type 1 reduces the incidence of heterosexual transmission. Arch Intern Med 1994; 154: 1971-76.
9 Operskalski EA, Stram DO, Busch MP, et al. Role of viral load in heterosexual transmission of human immunodeficiency virus type 1 by blood transfusion recipients. Am J Epidemiol 1997; 146: 655-61.
10 Fiore JR, Zhang Y, Bjorndal A, et al. Biological correlates of HIV-1 heterosexual transmission. AIDS 1997; 11: 1089-94.
11 Graziosi C, Pantaleo G. The multi-faceted personality of HIV. Nature 1997; 3: 1318-20.
12 Dean M, Carrington M, Winkler C, et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Science 1996; 273: 1856-62.
13 Zaitseva A. Blauvelt A, Lee S, et al. Expression and function of CCR5 and CXCR4 on human Langerhans cells and macrophages: implications for HIV primary infection. Nature 1997; 3: 1369-75.
14 Poss M, Martin HL, Kreiss JK, et al. Diversity in virus populations from genital secretions and peripheral blood from women recently infected with human immunodeficiency virus type 1. J Virol 1995; 69: 8118-22.
15 van't Wout AB, Kootstra NA, Mulder-Kampinga GA, et al. Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission. J Clin Invest 1994; 94: 2060-67.
16 Kunanusont C, Foy HM, Kreiss JK, et al. HIV-1 subtypes and male-to-female transmission in Thailand. Lancet 1995; 345: 1078-83.
17 Soto-Ramirez LE, Renjifo B, McLane MF, et al. HIV-1 Langerhans cell tropism associated with heterosexual transmission of HIV. Science 1996; 271: 1291-93.
18 Pope M, Ho DD, Moore JP, Weber J, Dittmar MT, Weiss RA. Different subtypes of HIV-1 and cutaneous dendritic cells. Science 1997; 278: 786-87.
19 Mazzaoli S, Trabattoni D, Lo Caputo S, et al. HIV-specific mucosal and cellular immunity in HIV-seronegative partners of HIV-seropositive individuals. Nature 1997; 3: 1250-57.
20 Shearer GM, Clerici M. Protective immunity against HIV infection: has nature done the experiment for us? Immunol Today 1996; 17: 21-24.
21 Wasserheit JN. Epidemiological synergy: interrelationships between human immunodeficiency virus infection and other sexually transmitted diseases. Sex Transm Dis 1992; 19: 61-77.
22 Dickerson MC, Johnston J, Delea TE, White A, Andrews E. The causal role for genital ulcer disease as a risk factor for transmission of human immunodeficiency virus: an application of the Bradford Hill criteria. Sex Transm Dis 1996; 23: 429-40.
23 Ho JL, He S, Hu A, et al. Neutrophils from human immunodeficiency virus (HIV)-seronegative donors induce HIV replication from HIV-infected patients' mononuclear cells and cell lines: an in vitro model of HIV transmission facilitated by Chlamydia trachomatis. J Exp Med 1997; 181: 1493-505.
24 Theus SA, Harrich DA, Gaynor R, Radolf D, Norgard MV. Treponema pallidum lipoproteins and synthetic lipoprotein analogues induce human immunodeficiency virus type 1 gene expression in monocytes via NF-kB activation. J Infect Dis 1998; 177: 941-50.
25 Rasmussen SJ, Eckmann L, Quayle AJ, et al. Secretion of proinflammatory cytokines by epithelial cells in response to chlamydia infection suggests a central role for epithelial cells in chlamydial pathogenesis. J Clin Invest 1997; 99: 77-87.
26 Eron JJ, Gilliam B, Fiscus S, Dyer J, Cohen MS. HIV-1 shedding and chlamydial urethritis. JAMA 1996; 275: 36.
27 Moss GB, Overbaugh J, Welch M, et al. Human immunodeficiency virus DNA in urethral secretions in men: association with gonococcal urethritis and CD4 cell depletion. J Infect Dis 1995; 172: 1469-74.
28 Cohen MS, Hoffman IF, Royce RA, et al. Reduction of concentration of HIV-1 in semen after treatment of urethritis: implications for prevention of sexual transmission of HIV-1. Lancet 1997; 349: 1868-73.
29 Dyer JR, Eron JJ, Hoffman IF, et al. Association of CD4 cell depletion and elevated blood and seminal plasma human immunodeficiency virus type 1 (HIV-1) RNA concentrations with genital ulcer disease in HIV-1-infected men in Malawi. J Infect Dis 1998; 177: 224-27.
30 John GC, Nduati RW, Mbori-Ngacha D, et al. Genital shedding of human immunodeficiency virus type 1 DNA during pregnancy: association with immunosuppression, abnormal cervical or vaginal discharge, and severe vitamin A deficiency. J Infect Dis 1997; 175: 57-62.
31 Levine WC, Pope V, Bhoomkar A, et al. Increase in endocervical CD4 lymphocytes among women with nonulcerative sexually transmitted diseases. J Infect Dis 1998; 177: 167-74.
32 Spear GT, Al-Harthi L, Sha B, et al. A potent activator of HIV-1 replication is present in the genital tract of a subset of HIV-1 infected and uninfected women. AIDS 1997; 11: 1319-26.
33 Grosskurth H, Mosha F, Todd J, et al. Impact of improved treatment of sexually transmitted diseases on HIV infection in rural Tanzania: randomised controlled trial. Lancet 1995; 346: 530-36.
34 Mayaud P, Mosha F, Todd J, et al. Improved treatment services significantly reduce the prevalence of sexually transmitted diseases in rural Tanzania: results of a randomized controlled trial. AIDS 1997; 11: 1873-80.
35 Wawer MJ, Gray RH, Quinn T. AIDS intervention in Uganda. Science 1995; 270: 564-65.
36 The World Bank (USA). Confronting AIDS: public priorities in a global epidemic. New York: Oxford University Press; 1997.
37 Gilson L, Mkanje R, Grosskurth H, et al. Cost-effectiveness of improved treatment services for sexually transmitted diseases in preventing HIV-1 infection in Mwanza Region, Tanzania. Lancet 1997; 350: 1805-09.
38 Sewankambo N, Gray RH, Wawer MJ, et al. HIV-1 infection associated with abnormal vaginal flora morphology and bacterial vaginosis. Lancet 1997; 350: 546-50.
39 Taha TE, Liomba G, Kumwenda N, et al. Association of bacterial vaginosis with HIV, preterm delivery and perinatal HIV infection [abstr B172]. Xth International Conference on AIDS and STD; 1997: Abidjan, Ivory Coast.
40 Cohen MS, Dallabetta G, Laga M, Holmes KK. A new deal in HIV prevention: lessons from the global approach. Ann Intern Med 1994; 120: 340-41.
41 Quinn TC, Glasser D, Cannon RO, et al. Human immunodeficiency virus infection among patients attending clinics for sexually transmitted diseases. N Engl J Med 1988; 318: 197-203.
42 Catchpole MA, Mercey DE, Nicoll A, et al. Continuing transmission of sexually transmitted diseases among patients infected with HIV-1 attending genitourinary medicine clinics in England and Wales. BMJ 1996; 312: 539-42.
43 Bersoff-Matcha SJ, Horgan MM, Stoner BP, Mundy LM, Fraser VJ. Sexually transmitted disease acquisition among HIV-infected women [abstr 546]. Infectious Diseases Society of America 35th Annual Meeting; 1997: San Francisco, CA, USA.
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