Women's Health Science Advances – FY 2016

NIAID conducts and supports research to prevent, diagnose, and treat infectious and immunological diseases that affect the health of women and girls.

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HIV/AIDS

Vaginal Ring Infused with Antiviral Drug Confers Partial Protection from HIV Infection

The ASPIRE study examined whether use of an intravaginal ring that continuously releases dapivirine, an experimental antiretroviral drug, could protect against HIV infection among women in sub-Saharan Africa. This double-blind study enrolled 2,629 women ages 18–45 years in Malawi, South Africa, Uganda, and Zimbabwe. Study participants received a vaginal ring that was replaced every 4 weeks and contained either dapivirine or placebo. All participants also received several HIV-prevention services, including counseling about how to protect against HIV infection and free condoms. At two study sites the investigators noted that the participants had low adherence to the ring protocol, as they were missing follow-up appointments or not using the ring consistently. After removing the data gathered from these two study sites, the researchers found that the dapivirine ring reduced the risk of HIV infection by 37 percent among all women. Overall, in women ages 25 and over, the ring lowered the risk of acquiring HIV by 61 percent. However, in an analysis that was not originally planned, the ring provided no protection for the 18–21 years age group. The disparities in results between age groups could be related to adherence to the ring protocol and/or age-related differences in susceptibility to HIV infection based on biological factors. Overall, the results indicate that use of the dapivirine vaginal ring could offer many women another option, in addition to oral pre-exposure prophylaxis, to protect against HIV infection. Increasing the available modes of prevention is especially important for women of sub-Saharan Africa, who are disproportionately affected by the global HIV epidemic.

Reference: Baeten JM et al. Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women N Engl J Med. 2016 Feb 22. [Epub ahead of print] News Release

Long-Term Use of the Antiretroviral Drug Tenofovir Is Associated with Reduced Kidney Function.

Tenofovir disoproxil fumarate (TDF) is an antiretroviral drug commonly used to treat and prevent HIV infection. Although TDF is tolerated well by most people, its use has been associated with reduced kidney function and more rarely, irreversible kidney damage. The level of TDF that is present in a person’s bloodstream depends on several factors including how well the drug is absorbed from the intestines and how fast the drug is metabolized by the body. These differences can result in different drug levels in the blood from person to person. As part of the ongoing Women’s Interagency HIV Study (WIHS), researchers identified TDF concentration as a major risk factor for TDF-induced kidney disease. The researchers evaluated 105 WIHS study participants who were prescribed 300 milligrams of TDF daily to control their HIV infection over a 7-year period. The study determined their individual TDF levels 0, 4, 8, 15, 18, and 24 hours after taking the drug. Researchers then evaluated patient kidney function by measuring blood creatinine levels every 6-months over the 7 years of follow-up. Patients with high creatinine levels have reduced kidney function. The results showed that women who had the highest concentration of blood TDF at 24 hours after dosing were the most likely to develop kidney damage. This study is the first to show directly that increased drug levels of TDF can lead to decreases in kidney function over time.

Reference: Baxi SM et al. Higher Tenofovir Exposure is Associated with Longitudinal Declines in Kidney Function in Women Living with HIV AIDS. 2016 Feb 20;30(4):609-18.

Analysis Reflects HIV Treatment Practices and Behaviors in Washington, DC

In order to identify factors that could help HIV-positive women achieve long-term suppression of the virus and reduce HIV transmission, scientists funded by NIAID used a predictive calculation called a trajectory analysis. Researchers analyzed data from 329 HIV-positive women living in Washington, DC, median age 35 years, who participated in four or more visits as part of the DC Women’s Interagency HIV Study (DC WIHS) between 1994 and 2012. The trajectory analysis was based on the probability, or likelihood, of detectable HIV in the bloodstream (viremia) over time. Using this method, the researchers characterized three distinct patient populations that varied in their patterns of blood viral loads over several time periods: approximately 40 percent of women had a high probability of being non-suppressed and viremic at each visit, a second group (36 percent) had a moderate risk of intermittent viremia, and a third group (24 percent) had a low risk of viremia during study follow-up.

The scientists found that those in the high-risk of viremia group were most likely to succumb to HIV/AIDS, with a 31 percent mortality rate. Women in the groups at moderate risk of viremia and at low risk of viremia on follow-up did not have significantly different mortality rates, at 6.9 and 4.7 percent, respectively. The researchers noted that despite the availability of antiretroviral therapies, only one-third of the women in the study maintained consistently low virus levels. DC WIHS is a community-based study and the findings likely reflect the characteristics and behaviors of participants in the Washington, DC, area and thus regional treatment successes and failures. The study highlights gaps in the success of treatment programs to fully suppress HIV and suggests that more tailored interventions may be needed to reduce HIV transmission, prevent the emergence of drug resistance, and improve outcomes of community HIV treatment programs.

Reference: Ocampo JM et al. Trajectory analyses of virologic outcomes reflecting community-based HIV treatment in Washington DC 1994-2012. BMC Public Health (2015) 15:1277.

Understanding Sex-Specific Differences in HIV Disease

HIV-infected women tend to have lower levels of the virus in their bloodstream (viral load) compared with men both before and after starting treatment with anti-HIV drugs. Yet HIV disease progresses at the same rate or faster in women than in men. To investigate possible reasons for these sex-specific differences, researchers looked at markers of immune activation and inflammation in 215 HIV-infected, treatment-naïve men and women from a diverse group of participants in the NIAID-funded multinational Prospective Evaluation of Antiretrovirals in Resource-Limited Settings trial. The researchers measured, in study participants who had suppressed HIV viral loads by week 24 of treatment, the levels of various markers in blood samples taken immediately before participants started on combination antiretroviral therapy (cART) for HIV, and at 24 and 48 weeks after starting treatment. The investigators found that, with treatment, women had greater increases in their CD4 T-cell counts, and either greater increases or less reduction in various key markers of inflammation and immune activation compared with men. These findings suggest that women experience less reduction in immune activation and inflammation than men in response to starting cART. Further studies with adequate numbers of women in the population being studied are needed to investigate whether this poorer cART-related response to reducing inflammation and immune activation has a significant impact on HIV-related mortality and other outcomes in women compared with men.

Reference: Mathad JS et al. Sex-related differences in inflammatory and immune activation markers before and after combined antiretroviral therapy initiation. J Acquir Immune Defic Syndr. 2016 Oct. 1;73(2):123–9.

Impact of Bacterial Vaginosis on Levels of Cervical Gamma Delta T Cells May Increase HIV Risk

Bacterial vaginosis (BV) is the most common infection of the female reproductive tract and occurs when the natural balance between strains of bacteria, or flora, in the vaginal tract is altered. Previous studies have shown that BV increases the risk of sexually transmitted infections, including the acquisition and transmission of HIV. However, the mechanism for this increased risk is not fully understood. A pilot study of women enrolled in the Miami Women’s Interagency HIV Study explored the relationship between BV and the levels of two types of gamma delta (GD) T cells, GD1 and GD2—important immune cells found in the female reproductive tract that may affect HIV acquisition. Researchers examined 17 HIV-infected women and 17 HIV-uninfected women who were at high risk of acquiring HIV. The levels of GD1 and GD2 T cells did not differ significantly between HIV-infected women with abnormal vaginal flora and those with normal flora. However, the study found that HIV-uninfected women with abnormal vaginal flora had lower levels of GD1 cells and higher levels of GD2 cells in the cervical region compared with HIV-uninfected women with normal vaginal flora. These findings suggest a possible mechanism for the increased risk of acquiring HIV, as lower levels of GD1 cells, which are an important first-line defense against infection, could be associated with a decreased early immune response to infection. Furthermore, higher levels of GD2 cells could increase the number of cells that can be targeted by HIV, since these cells have the CD4 and CCR5 cell-surface receptors that are needed for HIV to enter cells and establish infection.

Reference: Alcaide ML et al. Bacterial Vaginosis Is Associated with Loss of Gamma Delta T Cells in the Female Reproductive Tract in Women in the Miami Women Interagency HIV Study (WIHS): A Cross Sectional Study. PLoS One. 2016 Apr 14;11(4):e0153045.

Immunology

Ten Genes Newly Associated with the Heritability of Lupus among Asians

The autoimmune disease systemic lupus erythematosus (SLE, or lupus) is approximately ten times more common in women than in men. In addition, Asians have a higher SLE incidence, more severe disease, and greater risk of organ damage than people of European ancestry. Although SLE is known to have a strong genetic component, only about 10 percent of disease heritability is explained by previously identified genetic variations. To identify genetic variants associated with SLE in individuals of Asian ancestry, NIAID-funded researchers studied the DNA of 4,478 individuals with SLE and 12,656 unaffected individuals from six East Asian populations, focusing on immune-related regions, or loci, of the genome. They identified 10 loci newly associated with a predisposition for SLE and confirmed 20 regions previously suspected to be associated with SLE. They combined their data with those of previous studies to narrow these regions and identify gene variations most likely to cause or influence disease.

The proteins encoded by the genes the researchers identified were found to have a wide variety of functions; they included receptors on the cell surface, molecules that signal within and among cells, molecules that regulate expression of certain genes, and proteins involved in structural maintenance of the genome. One signaling molecule, an interleukin, is the target of a therapeutic already being studied in clinical trials for a different autoimmune disease, psoriasis. Other signaling molecules participate in pathways known to be dysregulated in lupus. Six of the ten newly identified genes are also associated with other autoimmune diseases. Together, these newly identified loci, together with previously identified loci, increase the explained heritability of SLE to 24 percent among individuals of Asian descent. These findings provide valuable insight into the pathogenesis and manifestations of lupus more broadly and point to new targets for SLE treatment and new drug development.

Reference: Sun C et al. High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. Nat Genet. 2016 Mar;48(3):323-30.

Systems-Level Analysis Identifies a Potential Biochemical Signature of Lupus

Toll-like receptors (TLR) are proteins involved in the initial recognition of microbes, and their activation leads to an inflammatory immune response. When TLRs recognize self-molecules (normal molecules of the body), the inflammatory immune response can lead to autoimmune diseases such as systemic lupus erythematosus (SLE, or lupus), which disproportionately affects women. To investigate how the response to TLR activation can vary across cells of the immune system, scientists initially analyzed blood samples from healthy volunteers. Using different types of stimuli to activate the TLR proteins, they measured changes in the expression patterns of immune signaling proteins by a sensitive method called mass cytometry, across eleven different immune cell types. The results of this system-wide analysis revealed distinct patterns of TLR-induced responses across different immune cell types. Similar analysis of immune cells from patients with newly diagnosed and untreated SLE revealed that a subset of white blood cells called monocytes produced increased levels of particular immune signaling proteins, compared with monocytes from healthy donors, defining a potential biochemical signature for SLE. These findings provide a systems-level framework that can be applied to study immune perturbations in people with inflammatory diseases such as SLE and might be used to help diagnose and treat these diseases.

Reference: O’Gorman WE et al. Single-cell systems-level analysis of human Toll-like receptor activation defines a chemokine signature in patients with systemic lupus erythematosus J Allergy Clin Immunol. 2015 Nov;136(5):1326-36.

Immune Cell Protein Ly9 Could be Target for Treating Lupus and Other Autoimmune Diseases

Systemic lupus erythematosus (SLE, or lupus) is an autoimmune disease in which the body’s immune system attacks healthy cells and tissues. The underlying molecular causes of lupus, which disproportionately affects women at a rate of approximately 10 women to every man, are not fully understood. However, lupus is associated with overactive B cells that produce autoantibodies— antibodies that target healthy cells and tissues. Previous research has shown that mice deficient in a protein called Ly9 spontaneously develop features of autoimmune disease, including the production of autoantibodies. Ly9 is a member of a family of proteins known as the SLAMF proteins, which are found on the surface of T and B cells and play a crucial role in regulating several immunological processes. Genetic variants of SLAMF are among the strongest predictors of lupus in both humans and mouse models of the disease. In this study, scientists investigated the role of Ly9 in the development and activity of antibody-producing B cells. They showed that, compared to normal mice, mutant mice lacking Ly9 had more marginal zone and B1 B cells, subsets of B cells that are particularly quick-responders and which, after immunization, produced more antibodies. This suggests that Ly9 normally helps hold these cells in check. Conversely, using an antibody that specifically activates Ly9 in normal mice, the scientists were able to selectively reduce the number of these B cells, which are often involved in autoimmune responses, as well as the production of antibodies from other B cells through a newly observed modulatory mechanism. The results suggest that Ly9 could be a promising target for the therapeutic treatment of autoimmune diseases such as lupus.

Reference: Cuenca M, Targeting of Ly9 (CD229) Disrupts Marginal Zone and B1 B Cell Homeostasis and Antibody Responses. J Immunol 2016; 196:726-737.

Infectious Diseases (Other Than HIV/AIDS)

A Novel 3D Culture System to Study the Development and Microbial Resistance of the Human Placenta

The human placenta is covered with a protective layer of multinucleated cells (cells with many nuclei) that serves as a barrier to prevent the transfer of toxins, bacteria, and viruses from mother to fetus. These specialized cells, called syncytiotrophoblasts (pronunciation: sin-SISH-ee-oh-TROH-fuh-blasts), are formed when precursor placental cells called trophoblasts fuse together. The molecular mechanisms that control the formation of syncytiotrophoblasts and protection from microbial infection are not well understood. To study these mechanisms, scientists devised a three-dimensional (3D) system for culturing (growing) cells that models placental development and function. When the researchers grew a commonly used cell line of human trophoblast cells known as JEG-3 cells on microscopic beads in a 3D bioreactor system, the JEG-3 cells fused together to form multinucleated cells and developed a dense border of tiny fingerlike projections called microvilli, much like mature syncytiotrophoblasts. JEG-3 cells grown in this system secreted placental hormones and exhibited a pattern of gene expression similar to cells derived from full-term human placentas. In addition, the 3D JEG-3 cell cultures, similar to what has been observed using cells derived from placenta in the first-trimester, were resistant to infection by viruses and Toxoplasma gondii, a parasite that can enter the placenta and is a major cause of congenital infections worldwide. This 3D cell culture model could thus provide a means to study the process by which trophoblasts fuse together to become syncytiotrophoblasts and develop resistance to microbial infection that protects the developing fetus. In addition, this culture system may be very useful in elucidating how some viruses, such as Zika virus, are able to penetrate the placental barrier and cause harm to the developing fetus.

Reference: McConkey CM et al. A three-dimensional culture system recapitulates placental syncytiotrophoblast development and microbial resistance. Sci. Adv. 2016 Mar 4;2(3):e1501462.

Estrogen Provides Women, but Not Men, Enhanced Protection Against Influenza

Influenza virus causes an acute respiratory infection in humans by entering and replicating in lung cells. Young women with influenza virus infections have more severe outcomes when compared with men of the same age. It is thought that hormones are responsible for sex-specific differences in response to influenza, especially since the severity of infection in females changes with respect to age and during pregnancy. To investigate these differences, researchers infected human nasal epithelial cell cultures with a seasonal influenza strain and studied how the infected cells responded to the female hormone estrogen, or to chemicals termed estrogenic compounds that mimic the actions of estrogen. The most potent natural form of estrogen is 17 beta-estradiol (E2), which is known to regulate cell function by reducing metabolic processes. Treatment of nasal cells with E2 reduced influenza virus replication and lowered virus levels in cells isolated from female, but not male, donors. FDA-approved compounds known to engage the estrogen receptor, such as raloxifene, and the environmental estrogen bisphenol A, also reduced influenza virus replication in nasal cells isolated from female but not male donors. The researchers also determined that the compounds initiated their antiviral effects through estrogen receptor beta, which is less prevalent on male cells. Estrogen had no effect on specific cellular antiviral pathways but dampened cell metabolic processes. Together, these results demonstrate that estrogen and estrogenic compounds have antiviral properties and can control cellular function in tissues outside the reproductive tract. Furthermore, this study suggests that FDA-approved therapeutic estrogenic compounds could be used to help treat influenza virus infections in women.

Reference: Peretz J, Estrogenic compounds reduce influenza A virus replication in primary human nasal epithelial cells derived from female, but not male, donors Am J Physiol Lung Cell Mol Physiol 2016, 310: L415–L425.

Home Screening for Bacterial Vaginosis to Prevent Sexually Transmitted Infections

Bacterial vaginosis (BV) is an infection that occurs when the natural balance between strains of bacteria in the vaginal tract is altered. While BV can cause symptoms and discomfort, a significant number of women with BV are asymptomatic. Previous studies have suggested that asymptomatic BV is associated with acquisition of sexually transmitted infections (STIs), including chlamydia and gonorrhea. However, the evidence is not conclusive, and current medical guidelines do not recommend treatment for asymptomatic BV.

To test whether home screening and treatment of asymptomatic BV could reduce the risk of vaginal chlamydia and gonorrhea infections, researchers studied 1,365 sexually active women ages 15–25 with asymptomatic BV who were also deemed at high risk for STIs. The women were randomly assigned to observation alone (the control group) or to treatment with a 7-day course of oral metronidazole—a medication commonly used to treat BV—at the start of the study and when a follow-up home testing sample was positive for BV. An additional objective of the study was to evaluate the use of home testing kits for the diagnosis of STIs. Women in both groups received home testing kits and provided samples in the form of vaginal swabs every 2 months for 12 months. The samples were tested for BV, chlamydia, and gonorrhea.

Women in both groups who tested positive for chlamydia and/or gonorrhea were notified and referred to a healthcare provider or a public STI clinic for treatment. Despite a reduced incidence of asymptomatic BV in the treatment group compared to the control group, there was no difference in the incidence of STIs between the two groups. Adherence to home screening was excellent (84–88 percent) in both groups. These findings show that home sampling is feasible and could provide more women with access to clinics that offer screening and treatment for STIs.

Reference: Schwebke JR, Home Screening for Bacterial Vaginosis to Prevent Sexually Transmitted Diseases Clin Infect. Dis 2016;62(5):531-6.

Mouse Model Mimics Human Malaria Infection During Pregnancy

Malaria infection during pregnancy can have severe consequences, such as severe anemia in the pregnant woman, stillbirth, low birth weight, and even death of the newborn. To better understand this disease during pregnancy, NIAID scientists established a new malaria pregnancy model in mice that mimics two processes common to humans during pregnancy: 1) re-emergence of a prior malaria infection and 2) infection with a new strain of malaria parasite following a pre-pregnancy infection with another strain. To model the first process, the scientists infected mice with the CB strain of the malaria parasite Plasmodium chabaudi (CB) and found that the parasite re-emerged during pregnancy in most mice. To model the second process, the scientists infected mice with the AS strain of Plasmodium chabaudi (AS) prior to pregnancy and then infected the mice again with the CB strain after the mice became pregnant. Both approaches led to infections with higher densities of CB parasites in the blood of pregnant mice than non-pregnant mice. These infections resulted in a variety of symptoms, including anemia and elevated levels of inflammation-causing factors called cytokines in the pregnant mouse, stillbirths and deaths of newborn mice, and lower weight and altered susceptibility to future infection in the offspring. Many of these symptoms mimic the human condition, suggesting that this mouse model will be useful for studying the mechanisms underlying malaria infection during human pregnancy.

Reference: Sharma A et al. Heterologous Infection of Pregnant Mice Induces Low Birth Weight and Modifies Offspring Susceptibility to Malaria. PLoS One. 2016 Jul 28;11(7):e0160120.

Progesterone Protects Female Mice Against Influenza Infection

Progesterone is a female hormone present in contraceptives used by more than 100 million women worldwide, and is known to have anti-inflammatory effects in the reproductive tract. But the role of progesterone in viral infections outside the reproductive tract is an open question. To investigate this question, scientists asked whether progesterone has any effect on influenza A virus (IAV) infection in mice. Mice that had their ovaries removed to deplete progesterone received either progesterone or placebo, and were subsequently infected with IAV. Both groups of mice became ill, and levels of influenza virus were the same in both groups. However, the progesterone-treated mice had less inflammation and tissue damage in the lungs, better lung function, and more rapid repair of inflammatory damage to the lung cells compared with mice that received placebo. Progesterone treatment elevated the number of immune cells known as T-helper cells and increased the levels of a growth factor called amphiregulin (AREG). The researchers subsequently boosted levels of AREG in female mice that lacked progesterone and showed that the AREG-treated mice had similar disease and recovery characteristics as those treated with progesterone. Conversely, in mice lacking AREG, progesterone treatment failed to protect against the effects of influenza infection. Progesterone treatment of mechanically damaged lung tissue also increased expression of AREG and enhanced wound repair. These findings suggest that progesterone stimulates tissue repair in the respiratory tract following influenza infection and show that sex hormones have notable health effects beyond the reproductive tract.

Reference: Hall OJ et al. Progesterone-based therapy protects against influenza by promoting lung repair and recovery in females. PLOS Pathogens. 2016 Sep 15;12(9):e1005840.

Non-Human Primate Model Shows Effects of Zika Infection on Developing Brain

The mosquito-transmitted Zika virus epidemic that spread through the Americas in 2015 and 2016 caused alarm because of its association with microcephaly—an abnormally small head resulting from an underdeveloped and/or damaged brain—among newborn babies. However, studies to test the relationship between fetal brain injury and Zika virus infection during pregnancy were hampered due to the lack of an animal model that closely mirrors Zika infection and fetal brain development in humans. To address this issue, researchers funded in part by NIAID studied Zika infection in a nonhuman primate that has placental structure and timing of fetal brain development similar to that of humans. They infected a pregnant pigtail macaque monkey with Zika virus at a time equivalent to the third trimester of human pregnancy, tracked fetal development after infection via sonograms and magnetic resonance imaging (MRI), and performed autopsies at a time equivalent to 38 weeks of human pregnancy to evaluate brain development and invasion of the Zika virus into the fetal brain.

The researchers found that Zika infection in the monkey closely resembled Zika infection in humans, with a similar pattern of virus invasion of the brain and associated brain developmental abnormalities. The results provided the first direct evidence that Zika virus can cross the placental barrier late in pregnancy and impair fetal brain development. The finding that fetal brain abnormalities in the monkey occurred within 10 days of Zika infection of the mother underscores the need for rapid treatment or preventive measures after a mosquito bite. Researchers hope that this animal model may serve as a valuable tool to test possible vaccines and treatments against the potentially serious effects of Zika infection on the developing fetus.

Reference: Adams Waldorf KA et al. Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate. Nature Medicine. 2016 Nov;22(11):1256–9.

Content last reviewed on January 6, 2017