Immune activation, inflammation and HIV acquisition risk
Richard Jefferys, TAG
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 – in the face of a mountain of evidence to the contrary – insists that non-sexual 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 analyse 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 werepresented 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 treatment of STDs could significantly reduce HIV acquisition risk but promising results from an initial randomised controlled trial were not confirmed by subsequent studies.  More recently, compelling evidence has emerged that inflammation and immune activation are critical factors underlying this apparent disconnect. 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 01 July 2012 issue of the Journal of Infectious Diseases, researchers in South Africa reportthat 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 that 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 recognise 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.” 
Source: TAG basic science web log. (21 Aug 2012).
- Allaisa L, Venter F. HIV, logic and sex in Africa. Preventive Medicine Volume 55, Issue 5, November 2012, Pages 401–404.
- Cohen CR et al. Increased levels of immune activation in the genital tract of healthy young women from sub-Saharan Africa. AIDS. 2010 August 24; 24(13): 2069–2074. doi: 10.1097/QAD.0b013e32833c323b.
- Naranbhai V et al. Innate Immune Activation Enhances HIV Acquisition in Women, Diminishing the Effectiveness of Tenofovir Microbicide Gel. J Infect Dis. (2012) doi: 10.1093/infdis/jis465. First published online: July 24, 2012.
- Roberts L et al. Genital Tract Inflammation in Women Participating in the CAPRISA TFV Microbicide Trial Who Became Infected with HIV: A Mechanism for Breakthrough Infection? 18th CROI, Boston 2011. Poster abstract 991.
- Mavedzenge SN et al. The association between Mycoplasma genitalium and HIV-1 acquisition among women in Zimbabwe and Uganda. AIDS. 26(5):617-624, March 13, 2012. doi: 10.1097/QAD.0b013e32834ff690.
- McGowin CL et al. Persistent Mycoplasma genitalium infection of human endocervical epithelial cells elicits chronic inflammatory cytokine secretion. Infection and Immunity Published ahead of print 20 August 2012, doi: 10.1128/ IAI.00819-12.
- Houlihan CF et al. Human papillomavirus infection and increased risk of HIV acquisition. A systematic review and meta-analysis. AIDS. 13 November 2012, Volume 26 (17); p 2211–2222 doi: 10.1097/QAD.0b013e328358d908.
- Padian N et al. Weighing the gold in the gold standard: challenges in HIV prevention research. AIDS: 13 March 2010 – Volume 24 – Issue 5 – p 621–635 doi: 10.1097/QAD.0b013e328337798a.
- See Jefferys R. Immune Surveillance Below the Radar: Study Offers Explanation for Acyclovir’s Failure to Reduce HIV Risk. TAG blog (August 2009).
- Koleka Mlisana K et al. Symptomatic Vaginal Discharge Is a Poor Predictor of Sexually Transmitted Infections and Genital Tract Inflammation in High-Risk Women in South Africa. J Infect Dis. (2012) 206 (1): 6-14. doi: 10.1093/infdis/jis298
- Cohen MS. Classical Sexually Transmitted Diseases Drive the Spread of HIV-1: Back to the Future. J Infect Dis. (2012) 206 (1): 1-2. doi: 10.1093/infdis/jis303