The perfect (cytokine) storm –genital inflammation and HIV

Take home messages on the importance of the genital mucosa in transmission and pathogenesis

Beginning with a plenary presentation on day one of the Australasian HIV&AIDS conference the complexity and importance of understanding the relationship between STIs and HIV was laid bare.

Associate professor Jo-Ann Passmore, from the University of Cape Town gave a fantastic presentation with a few key messages. She was presenting data on the vaginal mucosa of South African women prior to acquisition of HIV infection and the role of STIs:

• A healthy female genital mucosa is already an effective barrier to pathogens.

• Inflammation in the genitals exacerbates the likelihood of HIV establishing an infection as the cytokines draw in the very cells HIV needs to infect.

• The inflammation seen in the genitals is different compared to inflammation markers in the plasma.

• STIs are a driver of inflammation.

• There is heterogeneity between the various STI and inflammation (cytokine profiles) they induce.

•  Chlamydia, the most prevalent STI is very inflammatory.

• Using the inflammation markers, the researchers could identify 70% of HIV seroconverters.

Delving further into the proteins and associated inflammatory markers, Lyle Mckinnon presented data from the CAPRISA004 trial (Centre for the AIDS Programme of Research in South Africa), in Durban, South Africa which aimed to elucidate the mechanisms behind genital inflammation increasing HIV acquisition risk. They looked at the soluble mucosal proteome and associated cytokine expression in female Kenyan sex workers. Out of around 500 proteins measured, they found 3 that are involved in cell migration and 7 that decreased mucosal barrier function. These 10 proteins were the defining feature of women with elevated inflammatory cytokines and allowed them to predict which women had the highest inflammation.

Rather than being a helpful way to repair tissue and fight pathogens genital inflammation in this situation may be reducing the effective barrier of a healthy genital mucosa and increasing the risk of acquiring HIV. Genital inflammation may help to explain high rates of HIV transmission when the per –act transmission risk (1/1250 for vaginal intercourse) is low.

Next, Keith Fowke from the University of Manitoba gave a presentation on an innovative approach to reduce risk of HIV transmission – using low dose anti-inflammatory drugs.  

Keith set the scene by explaining that younger women have the highest risk of acquiring HIV based on their inflammation patterns and this may peak shortly after sexual debut or in the earlier years of sexual activity. Likewise, STIs are known to also be more inflammatory in younger people made worse by younger people having the highest rates!

In reference to female sex workers specifically; inflammation levels seem to decrease over time and markers of inflammation can increase from as little as a one month break from sex work. This suggests a model of mucosal tolerance over time with a peak risk of acquisition in between the stages of transactional sex and first identifying as a sex worker, arguably when these women are most at risk of acquiring HIV based on non-biological factors.

Taking this forward and with the acknowledgment that activated CD4+ T cells (caused by inflammation) are 1000x more susceptible to HIV infection than non activated cells it seems pertinent to consider modulating the inflammatory response as a prevention strategy.

The researchers identified 80 low risk women from Kenya and established baseline activation levels, then randomized them to take 6 weeks oral dose of either Aspirin (aka acetylsalicylic acid or ASA) or hydroxychloroquine (HCQ) which is used in the treatment of rheumatoid arthritis. They found a significant reduction in the percentage of CD4+ CCR5+ T cells in both PBMCS and cervical mononuclear cells (CMCs) for those taking aspirin and saw a similar reduction in CD4+ CCR5+ T cells in CMCs for those taking HCQ.

Besides the take home message that it works…..and aspirin in particular is already taken by many people around the world, the participants reported that taking the drugs were non-stigmatising, something which could have positive effects for adherence which in turn increases the efficacy of the prevention strategy.

Moving from one side of the perineum to the other, Andrew Harman from the Westmead Millennium Institute gave an informative and visually intriguing (pictures below) presentation on interventions at the mucosa or research working towards that end.

He outlined the research by first explaining about the large amount of heterogeneity between and within the immune cell subsets of the genital and anal tissues (dendritic cells in particular). Dendritic cells are of interest because of the role they play in transferring HIV from the epithelium to CD4 T cells.

Shockingly and relevant to the Australian epidemic concentrated amongst MSM, very little is known about the role  dendritic cells play in transferring HIV to CD4 T cells in the tissues of the colon and anus. This is in comparison to the female genital tract where the role of dendritic cells is much more understood.

The main reasons for this are that healthy human tissue is difficult to obtain, (especially anogenital tissues!) dendritic cells are hard to isolate and dissociate and even if they can be isolated, they are in small numbers.

So, over many years Andrew has had to establish collaborations with plastic surgeons, colorectal surgeons, urologists and gynaecologists to gain access to the full range of anogenital tissues – see image below for process of preparing human tissue. This has led to profiling of the various immune cell subsets in anogential tissues and in particular a novel population of rectal dendritic cells that can be identified by the combination of cell surface receptors proteins. If this can be characterised further it could lead to the translational goal of producing compounds that block these cell surface receptors, therefore preventing these cells playing a role in transferring HIV to CD4 T cells. Ideally a compound of this nature could be applied as a tissue type specific microbicide in the future – watch this space.