The geographic variation in the risk of HIV acquisition among heterosexuals has prompted extensive speculation and debate as to the underlying causes. The lack of a clear explanation has even fueled conspiracy theories, playing a prominent role in Thabo Mbeki’s disastrous embrace of AIDS denialism in South Africa and driving a campaign that insists—in the face of a mountain of evidence to the contrary—that nonsexual transmission is the answer. It has not helped that much of the research on the subject has focused on behavior, with hypotheses such those based on concurrent sexual partnerships being aggressively promoted by certain individuals even though many view the evidence supporting them as slim to non-existent (for a recent critique, see “HIV, logic and sex in Africa” by Lucy Allais and Francois Venter). Relatively speaking, biological explanations have received less attention, despite the fact that it is well known that the immunological environment in which HIV finds itself has a huge impact on its ability to replicate and thrive. Only a handful of published studies have looked at how geographic location can impact levels of immune activation, finding that background levels are significantly higher in locations on the African continent compared to Europe and the US. The first such study to specifically analyze immune activation in the genital tract (comparing women in Kisumu, Kenya and San Francisco, USA) was published only two years ago.
Several new papers report data potentially relevant to this topic. Researchers involved in the CAPRISA 004 trial, an evaluation of the preventive efficacy of a gel form of the antiretroviral tenofovir, describe results from an analysis of immune activation and HIV acquisition risk among trial participants (44 who acquired HIV infection and 37 who remained HIV-negative). Elevated systemic innate immune activation was a significant risk factor for HIV infection (odds ratio 11.27, 95% CI 1.84-69.09, p=0.009) while a quiescent innate immunity profile was associated with reduced risk (odds ratio 0.06, 95%CI 0.013-0.33, p=0.001). The data echo similar findings from a study of genital tract inflammation among CAPRISA 004 participants, which were presented at CROI in 2011 and further discussed at CROI this year by Quarraisha Abdool Karim. In those analyses, women with genital track inflammation were 14 times more likely to acquire HIV infection than those without. The researchers argue that strategies for dampening immune activation and inflammation should be considered in the context of biomedical HIV prevention research.
Among the potential causes of genital tract inflammation and immune activation, sexually transmitted diseases obviously stand out, and many STDs have been reported to significantly increase HIV acquisition risk (including HSV-2, gonorrhoea, chlamydial infection, trichomoniasis, and bacterial vaginosis). A more recent addition to this list is Mycoplasma genitalium, and a study just published online by the journal Infection and Immunity suggests that, unsurprisingly, this effect is likely mediated by increased inflammation.
The question of whether human papilloma virus (HPV) has a role in enhancing HIV acquisition has not been clearly answered, but a review and meta-analysis in the journal AIDS finds that the available evidence is consistent with a doubling in risk (although no associations with specific genotypes were detectable). The authors stress that the findings require validation, but note that three of the studies they reviewed contained sufficient data to estimate the proportion of HIV infections that may have been attributable to the presence of HPV infection at baseline: in women in Zimbabwe and South Africa, the figures were 21% and 37%, respectively, and in heterosexual men in Kenya the estimate was 28%. A recommendation that emerges from these analyses is that the effect of HPV vaccination programs on HIV incidence should be evaluated, particularly as vaccine coverage of HPV genotypes improves.
Unfortunately, unlike HPV, no vaccine exists for other STDs. At one time it was hoped that syndromic treatment of STDs could significantly reduce HIV acquisition risk but promising results from an initial randomized controlled trial were not confirmed by subsequent studies. Similarly, suppression of HSV-2 with acyclovir did not prove efficacious in reducing HIV incidence. More recently, compelling evidence has emerged that inflammation and immune activation are critical factors underlying these apparent disconnects. In the case of HSV-2, a detailed study revealed that numbers of CCR5-expressing CD4 T cells and DC-SIGN-expressing dendritic cells are elevated in the genital tract of infected individuals, and that acyclovir treatment does not significantly alter this environment.
In the July 1, 2012 issue of the Journal of Infectious Diseases, researchers in South Africa report that symptomatic vaginal discharge, a criteria for syndromic STD diagnosis, is in fact a poor predictor of inflammation and the presence of laboratory-diagnosed STDs. Furthermore, levels of inflammation were significantly elevated among women with laboratory-diagnosed STDs regardless of whether they were symptomatic or asymptomatic. The latter paper prompted a commentary from Myron Cohen entitled “Classical Sexually Transmitted Diseases Drive the Spread of HIV-1: Back to the Future.” Cohen concludes: “the ‘hidden epidemic’ of classical STDs is squarely blocking optimal prevention of HIV-1 transmission. These STDs—symptomatic or asymptomatic—simply cannot be ignored. As we commit to combination HIV-1 prevention, we must redouble our efforts to think of every possible way to recognize and treat classical STDs. Surely this problem is no more impossible to attack or less important than any other part of the HIV-1 pandemic.”
J Infect Dis. (2012)
First published online: July 24, 2012
Vivek Naranbhai1,2, Salim S. Abdool Karim1,3, Marcus Altfeld2,4, Natasha Samsunder1, Raveshni Durgiah2, Sengeziwe Sibeko1, Quarraisha Abdool Karim1,3, William H. Carr2,4 and the CAPRISA004 TRAPS team
1CAPRISA – Centre for the AIDS Programme of Research in South Africa
2HIV Pathogenesis Programme, Nelson R. Mandela School of Medicine, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa
3Department of Epidemiology, Mailman School of Public Health, Columbia University, New York
4Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Boston, Massachusetts
The antiretroviral agent, tenofovir, formulated as a vaginal microbicide gel, reduces human immunodeficiency virus (HIV) acquisition by 39% in women. This study assessed the role of preexisting immune activation in HIV acquisition in women from the CAPRISA 004 trial, to identify potential strategies to increase the effectiveness of tenofovir gel. Systemic cytokine and cellular immune mediators (platelets and natural killer [NK] cells) were assessed in women at high risk for HIV assigned to either tenofovir or placebo gel in the CAPRISA 004 trial. Notwithstanding tenofovir gel use, women who acquired HIV had significantly higher systemic innate immune activation prior to infection than women who remained uninfected. Activation of both soluble (cytokine) and cellular (NK cells) immune mediators were associated with HIV acquisition, individually or in combination. Hence, an innate immune activation suppressant could be added to tenofovir gel as a potential combination gel strategy in developing the next generation of higher efficacy antiretroviral microbicides.
Infection and Immunity Published ahead of print 20 August 2012, doi: 10.1128/IAI.00819-12
Chris L. McGowin1,#, Rochelle S. Annan1, Alison J. Quayle2, Sheila J. Greene2, Liang Ma1, Miriam M. Mancuso1, David Adegboye3 and David H. Martin1
1Department of Medicine; Section of Infectious Diseases, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
2Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
3Southern University at New Orleans, New Orleans, Louisiana, USA
Infection with Mycoplasma genitalium has been associated with male and female urogenital disease syndromes including urethritis, cervicitis, pelvic inflammatory disease (PID) and tubal-factor infertility. Basic investigations of mucosal cytotoxicity, microbial persistence and host immune responses are imperative to understanding these inflammatory urogenital syndromes, particularly in females considering the potential severity of upper tract infections. Herein, we report that M. genitalium can establish long-term infection of human endocervical epithelial cells that results in chronic inflammatory cytokine secretion and increased responsiveness to secondary toll-like receptor (TLR) stimulation. Using a novel quantitative PCR assay, M. genitalium was shown to replicate from 0-80 d post-inoculation (PI) during which, at most time points, the median ratio of M. genitalium organisms to host cells was ≤ 10 indicating that low organism burdens are capable of eliciting chronic inflammation in endocervical epithelial cells. This observation is consistent with clinical findings in women. Persistently-secreted cytokines predominately consisted of potent chemotactic and/or activating factors for phagocytes including IL-8, MCP-1 and MIP-1β. Despite persistent cytokine elaboration, no host cell cytotoxicity was observed except with super-physiologic loads of M. genitalium suggesting persistent infection occurs with minimal direct damage to the epithelium. However, it is hypothesized that chronic chemokine secretion with leukocyte trafficking to the epithelium could lead to significant inflammatory sequelae. Therefore, persistent M. genitalium infection could have important consequences for acquisition and/or pathogenesis of other STI, and perhaps explain the positive associations between this organism and Human Immunodeficiency Virus (HIV) shedding.
AIDS: POST ACCEPTANCE, 7 August 2012
Houlihan, Catherine F.; Larke, Natasha L.; Watson-Jones, Deborah; Smith-McCune, Karen K.; Shiboski, Stephen; Gravitt, Patti E.; Smith, Jennifer S.; Kuhn, Louise; Wang, Chunhui; Hayes, Richard
Objectives: Human papillomavirus (HPV), one of the commonest sexually transmitted infections, may be a cofactor in HIV acquisition. We systematically reviewed the evidence for an association of HPV infection with HIV acquisition in women, heterosexual men and men who have sex with men (MSM).
Design: Systematic review and meta-analysis.
Methods: Studies meeting inclusion criteria in Pubmed, Embase and conference abstracts up to 29/07/2011 were identified. Random effects meta-analyses were performed to calculate summary hazard ratios (HR). Publication bias and statistical heterogeneity were evaluated and population attributable fractions (PAFs) calculated.
Results: Eight papers were included, with previously unpublished data from five authors. Seven studies found an association between prevalent HPV and HIV acquisition. Risk of HIV acquisition in women doubled with prevalent HPV infection with any genotype (HR = 2.06 (95%CI = 1.44-2.94), I2 = 0%), although adjustment for confounders was often inadequate. The effect was similar for high-risk (HR = 1.99 (95%CI = 1.54-2.56), I2 = 8.4%) and low-risk (HR = 2.01 (95%CI = 1.27-3.20), I2 = 0%) HPV genotypes with weak evidence of publication bias (P = 0.06). Two studies in men were identified: both showed an association between HPV infection and HIV acquisition. Unpublished data from one of two studies in women indicated an association between genotypes targeted by HPV vaccines and HIV acquisition. PAFs for HIV attributable to infection with any HPV genotype ranged between 21% and 37%.
Conclusion: If further studies validate the association between HPV infection and HIV acquisition, HPV vaccines may reduce HIV incidence in high HPV prevalence populations, in addition to preventing cervical cancer. HIV surveillance studies during implementation of HPV vaccine programmes are warranted.
J Infect Dis. (2012) 206 (1): 6-14.
Koleka Mlisana1,2,3, Nivashnee Naicker1, Lise Werner1, Lindi Roberts4, Francois van Loggerenberg1, Cheryl Baxter1, Jo-Ann S. Passmore1,4,5, Anneke C. Grobler1, A. Willem Sturm6, Carolyn Williamson1,4,5, Katharina Ronacher7, Gerhard Walzl7 and Salim S. Abdool Karim1,8
1Centre for the AIDS Programme of Research in South Africa
2Department of Medical Microbiology, University of KwaZulu-Natal, Durban
3National Health Laboratory Service, Durban
4Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town
5National Health Laboratory Service, Cape Town
6Department of Infection Prevention and Control, University of KwaZulu-Natal, Durban
7Faculty of Health Sciences, University of Stellenbosch Medical School, Tygerberg, Cape Town, South Africa
8Department of Epidemiology, Columbia University, New York, New York
Background. Diagnosis and treatment of sexually transmitted infections (STIs) is a public health priority, particularly in regions where the incidence of human immunodeficiency virus (HIV) infection is high. In most developing countries, STIs are managed syndromically. We assessed the adequacy of syndromic diagnosis of STIs, compared with laboratory diagnosis of STIs, and evaluated the association between STI diagnosis and the risk of HIV acquisition in a cohort of high-risk women.
Methods. HIV-uninfected high-risk women (n = 242) were followed for 24 months. Symptoms of STIs were recorded, and laboratory diagnosis of common STI pathogens was conducted every 6 months. Forty-two cytokines were measured by Luminex in cervicovaginal lavage specimens at enrollment. Human immunodeficiency virus type 1 (HIV-1) infection was evaluated monthly.
Results. Only 12.3% of women (25 of 204) who had a laboratory-diagnosed, discharge-causing STI had clinically evident discharge. Vaginal discharge was thus a poor predictor of laboratory-diagnosed STIs (sensitivity, 12.3%; specificity, 93.8%). Cervicovaginal cytokine concentrations did not differ between women with asymptomatic STIs and those with symptomatic STIs and were elevated in women with asymptomatic STIs, compared with women with no STIs or bacterial vaginosis. Although laboratory-diagnosed STIs were associated with increased risk of HIV infection (hazard ratio, 3.3 [95% confidence interval, 1.5–7.2)], clinical symptoms were not.
Conclusions. Syndromic STI diagnosis dependent on vaginal discharge was poorly predictive of laboratory-diagnosed STI. Laboratory-diagnosed STIs were associated with increased susceptibility to HIV acquisition, while vaginal discharge was not.
J Infect Dis. (2012) 206 (1): 1-2.
Myron S. Cohen
Departments of Medicine, Microbiology and Immunology, and Epidemiology, The Schools of Medicine and Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina