Miranda Smith
Why HIV cure research needs to involve more women
Understanding how HIV cure interventions affect women will move us closer to the goal of an HIV cure for everyone.
Women and HIV
HIV is a women’s issue. Worldwide, more than half of the 36.7 million people living with HIV are women. That equates to 18.6 million women and girls. Each year, another 1 million new HIV infections adds to this tally. This makes HIV the leading global cause of death among women aged 30–49. These figures are intimately linked with gender inequality. Domestic violence, economic dependence, early marriage, lack of agency in health and poor access to education all contribute to the spread of HIV in women.
Women and HIV in Australia
In Australia, the picture is somewhat different. Here, women form a small (but significant) proportion of people living with HIV. Since 1984, about 8% of the 37,000 HIV diagnoses in Australia have been in women . This means there are about 3,000 women in Australia living with HIV, with around 100 women diagnosed each year for the last 10 years. Building support networks for and alliances among these women is not always easy. HIV status will often be the only common factor in women living with HIV who are otherwise different in age, background, marital status, parenting status and sexuality.
Features of HIV acquisition and diagnosis compound the impact of HIV in Australian women. The main risks for HIV diagnosis are having a partner at high risk of HIV infection or coming from a country with high levels of HIV. Most women acquire HIV through heterosexual sex. Getting HIV through heterosexual sex is a risk factor for late diagnosis. This means delayed access to treatment and increased risk of illness. It is estimated that around 13% of women with HIV in Australia are currently undiagnosed, compared with only 10% of men. Then we come to the increasing disparity of HIV infection in Aboriginal and Torres Strait Islander women. While the number of all women diagnosed with HIV in Australia is going down, diagnoses in Aboriginal and Torres Strait Islander women appear to be increasing. Aboriginal and Torres Strait Islander people are more likely to get HIV through heterosexual sex or injecting drug use than non-Indigenous people. This means more late diagnoses and less access to treatment and care.
Pregnancy can be a complicating factor for women, either heightening the risk of acquiring HIV or posing a transmission risk to the baby. New research from nearly 3,000 African couples presented this week at the Conference on Retroviruses and Opportunistic Infections (CROI) suggests that a woman’s risk of acquiring HIV through sex with a male partner living with HIV increases during pregnancy and is highest in the initial period after giving birth. For women living with HIV, there is also the possibility of passing the virus on to their baby. There are effective strategies available to manage this risk. These include effective antiretroviral treatment (ART) for the mother, possible preventive ART for the baby and feeding recommendations. Since 1984, 785 children have been born to women living with HIV in Australia. Fortunately, on this count, Australia is doing well. The transmission rate of HIV from mother to baby has dropped from 9% in 2007 to 0% in 2016.
How sex affects susceptibility to HIV
It is clear that the circumstances of women’s lives can dramatically influence their chance of becoming HIV positive. On a global level, these factors have a huge influence on why and how women become HIV positive.
Let’s look at three other ways that sex influences immunity and risk of infection.
1. X-chromosome genes
The X chromosome carries many immune-related genes. These genes include some of the immune activation machinery such as Toll-like receptor 7 (TLR7) and CD40 ligand (CD40L). They also include factors that control gene expression such as forkhead box P3 (FOXP3) . Men typically have one copy of the X chromosome. This means that if they have an X-linked gene mutation, it is in every cell in their body. Women typically have two X chromosomes, with each cell in the body randomly using just one. If a woman carries an X-linked gene mutation, it is present in roughly half her cells. The other half contain the non-mutated version. There are also many variants of X-linked genes. Men will have just one variant, whereas women can have two. The increased diversity of X-linked genes in women can make their immune system more responsive. This means less frequent and less severe infections with bacteria and viruses. The flipside is that women are more susceptible to some autoimmune conditions.
2. Sex hormones
The sex hormones, oestrogens, progesterone and testosterone, all impact on immunity. Women produce varying levels of all sex hormones and many immune cells, including T and B cells, express sex hormone receptors. Oestrogen and progesterone levels change during the menstrual cycle. High oestrogen levels in the early part of the cycle lead to more regulatory T cells and a subset of CD4 T cells that favour antibody production. Lower oestrogen levels later in the menstrual cycle lead to fewer regulatory T cells and CD4 T cells that promote cell-mediated immunity. Oestrogens and progesterone can influence immune functions in a number of ways. These include promoting or restricting the production of cytokines, receptors and activation pathways. For example, oestrogens can increase levels of CCR5, one of the HIV co-receptors, on the surface of CD4 T cells. Oral contraceptives or hormone-replacement therapy will have similar immune effects. The hormonal changes that occur with pregnancy also alter immune regulation and may worsen some conditions while improving others.
3. Anatomic differences
The female genital tract includes the labia, clitoris, vagina, cervix, uterus, fallopian tubes and ovaries. The female genital tract is a complex environment. The large mucosal surfaces comprise a complex mixture of cells including immune cells. Many features influence this environment, including the tissue structure, the microbiome (resident bacteria), the presence and consistency of mucous, acidity levels and the presence and activation status of immune cells. Many of these features block the entry of pathogens. The presence of CD4 T cells and other immune cells, however, mean that the female genital tract can be a welcoming environment for HIV.
HIV in women
HIV transmission in women mostly occurs through the genital tract during heterosexual sex. The large mucosal surface, the presence of cells with HIV co-receptors and elevated levels of immune activation all favour HIV transmission. Micro-abrasions and tears which can occur in the vagina and cervix from sexual intercourse increase the chance of transmission by reducing the natural barriers to infection. The occurrence of other sexually transmitted infections such as Human Papilloma Virus (HPV), symptomatic Candida albicans infection, Herpes simplex type-2 (HSV-2) and Trichomonas vaginalis also increase the risk of HIV transmission through altering the inflammatory environment and causing changes to the mucosal surfaces.
HIV infection in women can look different to HIV infection in men. Women may experience fewer symptoms in acute HIV, leading to later diagnosis.
Women living with HIV typically have up to 40% lower HIV viral loads and higher CD4 T cell counts than men. These features would suggest a milder disease course, but actually women display higher levels of immune activation and progress to acquired immunodeficiency syndrome (AIDS) faster than men with the same viral load. Recent research suggests that bone mineral density (BMD) declines twice as fast in women with HIV than men. BMD loss is a risk factor for bone fractures and is a major feature of osteoporosis.
HIV viral loads are typically measured in the peripheral blood plasma, the liquid component of blood that circulates in the body. Peripheral blood is, however, not the only bodily fluid to harbour HIV. The virus is also found in other secretions such as vaginal fluid, breastmilk and menstrual blood. The data on viral load in these other secretions is nowhere near as well studied as peripheral blood.
While not every aspect of HIV infection in women has been studied, it is known that for sexual transmission, undetectable equals untransmissible (U=U). Women living with HIV who have access to ART, are able to take treatment regularly and who have undetectable viral loads cannot transmit HIV to their sexual partners. Women with partners living with HIV cannot acquire HIV if their partner is on ART and has an undetectable viral load. Access and adherence to antiretroviral therapy is clearly the critical factor in controlling HIV infection and the risk of transmission.
Why we need women in HIV cure research
HIV is clearly a women’s issue, and research towards an HIV cure needs to involve women. Involving the full spectrum of people living with HIV in research towards an HIV cure is one way of breaking down HIV stigma. This involvement also provides evidence for improved treatment or other interventions in diverse populations.
Women with childbearing potential are often excluded from participating in research studies, and particularly from research studies on HIV cure. Viewing reproductive ability solely as an exclusion category for research is clearly unacceptable. Efforts need to be made to ensure that women with HIV can make informed choices about their reproductive rights and their rights to participate in research studies.
There are a lot of unanswered questions about HIV persistence, HIV reservoirs and the effect of interventions directed towards curing HIV in women. These include:
- Is HIV latency established and maintained the same way in men and women? If not, why not?
- Are HIV reservoirs the same in men and women? Assess size, composition, location, susceptibility to reactivation etc.
- What impact does the menstrual cycle (or other hormonal changes) have on the HIV reservoir? Do hormones affect the efficacy of interventions such as latency-reversing agents?
- How does the HIV reservoir change over a lifetime, especially through changes associated with hormonal adjustments e.g. adolescence, menopause?
As a start, researchers should be required to report the sex breakdown of their study populations. This year’s CROI conference requires presenters to
consider whether there is substantive evidence of differences in effect by sex or other key demographic groups. If so, a stratified analysis should be made available during the presentation of the abstract at CROI.
This approach should become the norm for all conference presentations and publication.
Further efforts are needed to increase the number of women involved in HIV cure research studies. This may require more than just the removal of exclusionary criteria. For example, there may be specific logistical barriers that prevent women from enrolling in clinical studies which will need to be addressed. We have to begin by ensuring that women are included in research discussions and are valued as critical partners in research studies. Work towards an HIV cure needs to address the whole spectrum of diversity of people living with HIV. Actively involving women in HIV cure research will be an important step towards an HIV cure for everyone.
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